An excerpt from 50 Studies Every Hospitalist Should Know.

The DOSE trial provided good insight into the dosage and frequency for administering loop diuretics in patients presenting with acute decompensated heart failure. Physicians can prescribe intravenous loop diuretics with confidence that their decision is evidence-based, efficacious, and safe.

Research questions

Among patients with hemodynamically stable, acute-on-chronic heart failure with baseline loop diuretic use, the study sought to answer two key questions:

• Does conversion of baseline diuretics to equivalent intravenous (IV) dose vs. 2.5 times dose escalation result in significant differences in 72-hour symptom assessment and serum creatinine?
• Does administration in twice-daily bolus vs. continuous infusion result in significant differences in 72-hour symptom assessment and serum creatinine?

Study overview

Conducted between 2008 and 2009 across 26 clinical sites in the United States and Canada, the study enrolled 308 subjects (planned 300). Participants were inpatients at least 18 years old with preexisting heart failure who required an equivalent daily oral dose of furosemide 80 mg to 240 mg for at least one month. They were identified within 24 hours of admission as having signs or symptoms of volume overload with an anticipated need for 48 or more hours of IV loop diuretics.

Exclusion criteria included low B-type natriuretic peptide (BNP) levels, dialysis, baseline serum creatinine greater than 3.0 mg/dL, acute coronary syndrome within four weeks, hypotension (systolic blood pressure less than 90 mmHg), sepsis, or specific cardiac conditions like restrictive cardiomyopathy.

The study utilized a 2 × 2 factorial design: randomized, controlled, double-blind, and double-dummy.

• Low-dose group: Each subject received the IV furosemide dose equivalent to their outpatient total daily oral loop diuretic dose.
• High-dose group: Each subject received 2.5 times the IV equivalent of their total daily oral loop diuretic dose.

Both groups were fractionated into every-12-hour or continuous infusion dosing strategies.

Results

Baseline characteristics were well balanced among the four groups, with an average age of approximately 66 years old. Mean left ventricular ejection fraction was 35 percent, with approximately 57 percent having ischemic cardiomyopathy.

The results showed no significant interaction between the mode of administration and the dosing strategy for the primary endpoints.

• Symptom relief: There was no difference in the likelihood of switching to oral diuretics at 48 hours between the continuous infusion and bolus groups. However, subjects assigned to the high-dose strategy were more likely to change to oral diuretics at 48 hours than those in the low-dose strategy (31 percent vs. 17 percent).
• Dosing: The median total dose of IV furosemide equivalent over 72 hours for those in the low-dose vs. high-dose arms was 358 mg vs. 773 mg.
• Renal function: While there was a greater mean increase in creatinine as well as a proportion with renal dysfunction in subjects in the high-dose arm, by 60 days out there was no significant difference in renal function between subjects in the high-dose and low-dose arms. There was no significant difference in renal function in infusion vs. bolus dosing.

Criticisms and limitations

Despite the prevalence of prior hospitalizations, this was, on average, a low-acuity cohort, as evidenced by lack of tachycardia, normotension, normal sodium levels, and modest renal dysfunction. The results cannot necessarily be generalized to sicker patients presenting with decompensated heart failure, who might be more likely to have diuretic resistance.

The dosing regimens may not be representative of typical practice, particularly for infusions where much higher doses are often used to achieve and maintain adequate diuresis.

Assessing at 72 hours might be too early to differentiate outcomes, particularly given crossover being allowed at 48 hours. This was an ethically challenging limitation to avoid, however, given it being good clinical practice to check on dose efficacy and adjust after each dose.

Summary and implications

While even prior to the DOSE trial it was already known that higher doses of loop diuretics would be more likely to produce effective diuresis than lower doses, the DOSE trial helped to characterize how creatinine increases from higher doses are temporary and not a reason to de-escalate diuresis, paving the way for broad acceptance of the often-cited “rule of thumb” to double the oral diuretic dose to initiate diuresis as an inpatient.

It did temper enthusiasm for use of costlier, more burdensome continuous infusions over bolus dosing. However, the study limitations noted above do suggest that infusions may still have a role in patients with greater diuretic resistance, at higher doses, and with more aggressive titration.

Clinical case: bolus vs. continuous infusion

Case history: Mr. An is a 66-year-old gentleman with history notable for remote non-ST segment elevation myocardial infarction, status post drug-eluting stent placement in the left anterior descending artery complicated by ischemic cardiomyopathy with left ventricular ejection fraction persistently 45 percent. He is on a long-standing home regimen of oral furosemide 80 mg twice daily, in addition to guideline-directed medical therapy.

He presents because he simply could not catch his breath even sitting upright in his recliner, after experiencing two weeks of progressive dyspnea, pedal edema, and early satiety after running out of his diuretics while traveling across the country. He denies cough, fevers, chest discomfort, or lightheadedness.

In the emergency department, he is noted with heart rate 86 beats per minute, blood pressure of 100/60 mmHg, oxygen saturation of 92 percent on 3 L of nasal cannula, and weight 85 kg (6 kg above baseline). His jugular venous pressure is 14 to 16 cmH2O; cardiac examination discloses regular rate and rhythm with S3 but no murmurs; chest auscultation shows crackles up to midlung; and his legs are warm with pitting edema up to the midshin. His labs are notable for a creatinine similar to his baseline (0.9 mg/dL) and BNP 5,000 with no prior value for comparison.

He is eager to get home by the end of the week for his daughter’s piano recital and asks, “What is the best way to get the water out of my lungs and legs fast? And I have got a history of kidney failure in the family; how do we prevent my ending up on dialysis?”

Suggested answer: The results of the DOSE trial suggest that in hemodynamically stable patients with acute-on-chronic heart failure like Mr. An, continuous dosing vs. every-12-hour dosing of diuretics does not result in significant differences in global symptom relief or renal function. Increasing to 2.5 times equivalent of the oral dose (i.e., 200 mg IV furosemide twice daily) may improve net diuresis and symptom relief with only transient changes in creatinine.

While the study allowed dose adjustment after 48 hours, it is prudent to evaluate after each dose to ensure appropriate diuresis. From a patient-centered perspective, twice daily dosing may be more desirable than continuous infusion (i.e., furosemide at 16 mg/hour) in eliminating tethering to IV poles.

Benjamin P. Geisler, Jeffrey L. Greenwald, and Kathy May Tran are internal medicine physicians. They are authors of 50 Studies Every Hospitalist Should Know.