How to Diurese in Acute HF: Dosing Strategies Get an Evidence Base

March 17, 2010

March 17, 2010 (Atlanta, Georgia) — Whether loop diuretics are given in a continuous infusion or intermittently or at conventional or high doses appears to make little difference in their effectiveness at relieving symptoms in patients hospitalized with acute heart failure, according to a study that, its investigators say, also suggests high-dose diuretics in that setting are safe. The trial was billed as the first randomized, controlled exploration of a management strategy that's been a mainstay for decades without much of a supporting evidence base to guide how it's performed.

Dr G Michael Felker

The trial, called Diuretic Optimization Strategies Evaluation (DOSE), separately randomized its 308 predominantly male patients to receive intravenous furosemide at "low" vs "high" doses and in a continuous infusion vs a bolus every 12 hours and found no evidence to support concerns, based on observational data, that high-dose diuretics damage the kidneys and shorten survival, observed Dr G Michael Felker (Duke Clinical Research Institute, Durham, NC) when presenting it here at the American College of Cardiology (ACC) 2010 Scientific Sessions.

Importantly, treating physicians in the trial had the discretion to adjust diuretic strategies based on clinical responses after the patients had been managed for 48 hours according to their randomization assignment.

Felker, who is co–principal investigator for the study, observed that the high-dose strategy did cause some renal dysfunction, but it reversed within a week. There was also no evidence for increased risk of clinical events at 60 days after high-dose therapy or after low-dose, continuous, or intermittent diuretic therapy, he said, cautioning that the trial wasn't powered for differences in clinical outcomes.

On the other hand, patients in the high-dose group, compared with the low-dose group, showed significant improvements in a series of secondary end points assessed at 72 hours, including weight loss, heart-failure biomarkers, and dyspnea, and favorable trends in other secondary measures.

A Guide for Contemporary Practice?

In the discussion period after his presentation, Felker emphasized that the trial's primary message comes from the primary outcomes, which show no differences among the different dosing strategies. Still, he added, "I do think that this trial is a little different from a lot of placebo-controlled trials that we do, because obviously tomorrow patients all over will come into the hospital with decompensated heart failure, and physicians are going to have to make decisions about how to give diuretics."

In the trial as a whole, "there are a lot of suggestions that you get quicker, more favorable results with a high dose--greater symptom relief, greater decongestion based on physical signs," Felker said, acknowledging that those findings are based on secondary end points. DOSE also suggests that "an every-12-hour bolus, which is a traditional way to give diuretics, seems to be certainly just as good as continuous."

Dr Christopher O'Connor

At a briefing on DOSE for reporters, co–principal investigator Dr Christopher O'Connor (Duke University Medical Center, Durham, NC) agreed that the "very proper statistical conclusion from this study is that there was no difference." But he also agreed that the promising secondary findings suggest some possible advantages for the high-dose approach that are actionable right away. "Sometimes [we] have to make decisions based on imperfect data, based on trends, based on secondary end points--and this is the best available data in the world today on how to choose a [loop-diuretic] dose."

As a panelist assigned to discuss Felker's presentation, Dr Mandeep R Mehra (University of Maryland School of Medicine, Baltimore) said firmly that the appropriate conclusion from the trial, based on the primary end-point outcomes, "is that there is no difference in either low or high [dosing] or continuous vs bolus infusion."

Dr Mandeep R Mehra

That conclusion could be interpreted as suggesting that "it's perhaps better start low and go slow, because one of the critical facets in the way your study was constructed allowed the clinic to change its strategy at the 48-hour point," Mehra added.

"In my opinion," he said, "this important study tells us that, in this narrow group of heart-failure patients who are on high background doses of diuretics at the time of inception, a strategy of a low initial dose of diuretics, given as a bolus, works just fine as long as you have the opportunity to reevaluate the dosing structure at the two-day time point."

The trial was conducted at centers in the US and Canada and randomized 308 acute heart-failure patients with a prior diagnosis of chronic heart failure and daily outpatient use of oral loop diuretics (80 mg to 240 mg) for at least one month; the mean daily dose was 131 mg/day. Patients with serum creatinine >3.0 mg/dL were excluded, as were those for whom coronary angiography was anticipated.

The randomizations were "double-blind, double-dummy," in that all patients received both continuous and intermittent dosing, with one including furosemide and the other serving as a placebo. Of the 156 patients assigned to intermittent dosing, 74 and 82 received low- and high-dose furosemide, respectively; of the 152 assigned to continuous dosing, 77 received the low dose and 75 the high dose.

"Low dose" corresponded to the patient's oral dose, and "high dose" meant 2.5 times the oral dose.

At 48 hours, patients were reassessed and either switched to oral diuretics, continued on their assigned regimen, or had their doses increased by 50% while blinding was maintained, Felker reported.

Symptoms as gauged by patient global assessment at 72 hours, the primary efficacy end point, weren't significantly different between the intermittent and continuous dosing groups (p=0.47). The high-dose strategy trended toward greater symptom improvement (p=0.06).

The change in creatinine from baseline to 72 hours, the primary safety end point, was +0.05 mg/dL for intermittent dosing and +0.07 mg/dL for continuous dosing (p=0.45). It was +0.04 mg/dL in the low-dose group and +0.08 mg/dL in the high-dose group (p=0.21).

There were no significant differences or notable trends in secondary end points between patients receiving intermittent vs continuous dosing. But some emerged in the low- vs high-dose analysis.

Secondary Outcomes at 72-Hour Assessment in DOSE, Low-Dose vs High-Dose Groups

Outcome Low-dose, n=151 High dose, n=157 p
Dyspnea self-assessment, AUC 4478 4668 0.041
Congestion-free (%) 11 18 0.091
Change in weight (lbs) -6.1 -8.7 0.011
Net volume loss (mL) 3575 4899 0.001
Change in NT-proBNP level (pg/mL) -1194 -1882 0.06
Cr increase >3 mg/dL (%) 14 23 0.041

AUC=area under the curve for graphed patient global assessment

NT-proBNP=amino-terminal pro-B-type natriuretic peptide


The secondary end-point advantages in the high-dose group came at the cost of a greater risk of worsening renal function, defined as a >3 mg/dL rise in creatinine. Overall, according to Felker, "those changes appeared to be transient, such that differences between the groups diminished over time. And by day 7 or discharge, and certainly by day 60, there was no longer any substantial signal of greater renal dysfunction with high-dose [diuretics]."

And the DOSE investigators are confident that there were no other signals of harm from the high-dose diuretic approach. To heartwire , O'Connor acknowledged that the limited size of the population "challenges the robustness of the clinical end points." Still, he pointed out, there was no significant elevated risk of adverse events at 60 days.

The hazard ratio for death, rehospitalization, or an emergency-department visit at 60 days was 1.19 (95% CI 0.86-1.66, p=0.30) for continuous vs every-12-hour dosing and 0.83 (95% CI 0.60-1.16, p=0.28) for high-dose vs low-dose.

The confidence intervals are broad, O'Connor noted, "but it's obviously encouraging that there wasn't harm from any issues that incurred in the in-hospital setting, particularly that transient creatinine change at 72 hours."

A full 51% of the DOSE population had diabetes and therefore might be especially vulnerable to the adverse effects of loop diuretics, which can increase diabetic risk; the investigators didn't present an outcomes analysis by subgroups.

"I think the best way to look at the diabetic subset is to look at the overall results of the trial, and that would suggest that there's probably no issue for that cohort," O'Connor said.

Mehra seemed to agree with the investigators' safety assessment. Felker's presentation, he said, "showed very nicely" that the creatinine elevations were reversible and didn't increase risk.

Dr James McClurken

In an interview, ACC program chair Dr James McClurken (Temple University, Philadelphia, PA), who moderated the press briefing, said that, to be safe, he would exclude diabetics with acute heart failure from receiving high-dose diuretics. "I think the other group where there should be caution would be those who come in with acute heart failure for the first time, and they wind up being catheterized." Cardiac catheterization with radiographic contrast would entail hydration to help protect the kidneys, he observed for heartwire .

"So now you want to hydrate them, but also give diuretics. It can become a bit of a juggling act," he said. High- rather than low-dose diuretics would only make that situation trickier.

As for the "transient" creatinine elevations, McClurken said he would have preferred to see a longer follow-up time in the trial. However, he noted, such elevations in this setting are not uncommon, and he "feels reasonably comfortable" with the DOSE investigators' interpretation that they did not increase risk.

Felker reports receiving consulting fees or honoraria from Corthera and research grants from Roche Diagnostics, Amgen, and Cytokinetics. Mehra discloses consulting fees or honoraria from Medtronic, St Jude Medical, Boston Scientific, Solvay, and Geron. O'Connor and McClurken have no disclosures.


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