DOSE Trial Published: How to Give IV Diuretics in Acute HF

March 04, 2011

March 4, 2011 (Boston, Massachusetts) — After years of concern that high-dose IV diuretics might compromise the kidneys and even survival compared with low-level dosing in acute decompensated heart failure (ADHF) and uncertainty over the efficacy of intermittent IV bolus compared with continuous administration, there is a published major randomized trial to provide solid guidance [1].

For the most part, it doesn't matter, according to the Diuretic Optimization Strategies Evaluation (DOSE): Whether furosemide was given "high dose" or "low dose" or in intermittent bolus or continuous infusions, there were no significant differences in the trial's primary measures of symptom relief or short-term impact on renal function.

And although the finding carries less weight, neither dosage nor mode of administration made a difference to a secondary composite clinical end point at 60 days.

DOSE is published in the March 3, 2011 issue of the New England Journal of Medicine with co–primary investigator Dr G Michael Felker (Duke Clinical Research Institute, Durham, NC) as the first author. He had unveiled the trial's major findings last year at the American College of Cardiology 2010 Scientific Sessions, reported at that time by heartwire .

The story from DOSE . . . is that aggressive decongestion is a critical part of achieving good outcomes in acute heart failure.

Felker pointed out for heartwire that DOSE nevertheless showed some differences, especially between patients who received furosemide at the two dosage levels. Moreover, the 308-patient trial's primary and secondary findings as a whole may favor the high-dose option, which relieved dyspnea better, led to more weight and fluid volume loss, and pushed natriuretic peptide levels further down--although the latter finding fell just short of significance.

All that may have come at the cost of worsening renal function: more high-dose than low-dose patients showed a jump in serum creatinine to >0.3 mg/dL at any time in the first 72 hours of therapy, a secondary but prespecified safety end point.

Consistent with other trials and observational data, according to Felker, "in DOSE we saw a transient worsening of renal function in the higher-dose arm, but it was quite transient, meaning it was completely gone by day of discharge, and it didn't seem to have any adverse downstream implications in terms of postdischarge outcomes." So," he said, "if you look across the totality of end points, high-dose definitely seems to show a strong signal that it's preferable to low-dose."

As for continuous vs intermittent bolus dosing, no significant differences or noteworthy trends favoring either strategy were seen.

DOSE Co–Primary End Points, Changes From Baseline to 72 Hours, Intermittent-Bolus vs Continuous-Infusion Groups

Primary end point Intermittent bolus, n=156 Continuous infusion, n=152 p
Global symptom assessment (AUC) 4236 4373 0.47
Mean change creatinine (mg/dL) +0.05 +0.07 0.45

AUC=area under the curve of serial assessments using visual analog scale

Since his oral presentation of DOSE almost a year ago, Felker said that "anecdotally, I've seen that fewer people are using continuous infusion. I think there [had been] a strong belief by a lot of people, including me, that continuous infusion was probably a better way to give it." And that seems to be wrong, he said: clinically, it's no better and no worse.

Conceivably, though, some types of patients might fare better with one dose level or dosing strategy than another. For example, high-dose furosemide might not be as good for some higher-risk patients such as diabetics. Felker said there was no evidence in the trial for differences by patient subgroups. But since there was parity for the safety and efficacy end points, he noted that the trial seems to leave room for tailored decisions on what regimen might be best based on perceived patient risk.

DOSE Co–Primary End Points, Changes From Baseline to 72 Hours, Low-Dose vs High-Dose Strategies

Primary end point Low dose, n=151 High dose, n=157 p
Global symptom assessment (AUC) 4171 4430 0.06
Mean change creatinine (mg/dL) 0.04 0.08 0.21

AUC=area under the curve of serial assessments using visual analog scale

An accompanying editorial echoed Felker's take on the study [2]. The trial showed no greater benefit from the commonly used continuous-infusion strategy, and high-dose furosemide "did not substantially worsen renal function," observes Dr Gregg C Fonarow (Ronald Reagan University of California, Los Angeles Medical Center).

"Both of these findings should change current practice," he writes. "Since a high-dose regimen may relieve dyspnea more quickly without adverse effects on renal function, that regimen is preferable to a low-dose regimen. Administration of boluses may be more convenient than continuous-infusion and equally effective."

DOSE Secondary End Points at 72 Hours, Low-Dose vs High-Dose Strategies

Secondary end point Low dose, n=151 High dose, n=157 p
Dyspnea self-assessment (AUC) 4478 4668 0.04
Freedom from congestion (%) 11 18 0.09
Net fluid loss (mL) 3575 4899 0.001
Change in creatinine >0.3 mg/dL (%) 14 23 0.04

AUC=area under the curve of serial assessments using visual analog scale

DOSE assigned the mostly white, mostly male patients with ADHF to the two dosages and two administration methods in separate randomizations. Entry required a history of chronic heart failure and treatment with at least one oral loop diuretic throughout the previous month (80-240 mg/day furosemide or equivalent of a different agent).

The low-dose and high-dose strategies were defined as daily total IV furosemide equal to or 2.5 times the daily oral dose, respectively. Bolus dosing meant an IV bolus every 12 hours. At 48 hours, physicians could choose to increase blinded therapy by 50%, make no changes to administration, or withdraw blinded IV therapy and give patients oral diuretics on an open-label basis. At 72 hours, "all treatment was open-label at the discretion of the treating physician," who remained blinded as to prior treatment assignment.

Hazard Ratios for Clinical Composite Secondary End Point* at 60 Days for Both Randomizations

Randomization HR (95% CI) p
Continuous vs bolus 1.15 (0.83–1.60) 0.41
High vs low dose 0.83 (0.60–1.16) 0.28

*Death, rehospitalization, or emergency-department visit

"Since this trial was not powered to detect differences in the rates of death or rehospitalization, the effects of loop diuretics on clinical events in patients with heart failure remain unknown, despite the fact that these drugs have been in the treatment armamentarium for more than 50 years," observes Fonarow in his editorial.

Felker said the trial, considered with other evidence, has a message regarding the effects of loop diuretics and other drugs used or tested in ADHF: treatments that are better at relieving congestion seem to be associated with better outcomes.

For example, he said, clinicians "might be worried about worsening renal function and therefore might not decongest the patient as aggressively, and I think that would be a mistake. The story from DOSE and some observational studies is that aggressive decongestion is a critical part of achieving good outcomes in acute heart failure. It may seem to come at the cost of transient worsening renal function, but that doesn't seem to be a major problem, as long as it's monitored carefully."

Felker reports receiving consulting fees from Amgen, Cytokinetics, Corthera, Otsuka, Novartis, and Roche Diagnostics and grant support from Amgen, Cytokinetics, Otsuka, and Roche Diagnostics; disclosures for the coauthors are listed in the paper. Fonarow reports consulting for Novartis and Scios.

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