Added to Diuretics, Low-Dose Dopamine Renoprotective in Small Acute-HF Trial

September 21, 2009

September 21, 2009 (Boston, Massachusetts) With newer drugs bombing out so frequently in acute decompensated heart failure (ADHF) randomized trials, some that have been around a while are looking "distinguished" with age, rather than old.

Adding a little dopamine to reduced-dose diuretics might provide as much diuresis as full-dose diuretics on their own in patients with ADHF, without the potassium-draining and potentially kidney-damaging effects of loop diuretics, suggest preliminary data from some of the first patients enrolled in an ongoing randomized trial [1].

Dr Fillippos Triposkiadis (Larissa University Hospital, Greece) reported the findings from the Dopamine in Acute Decompensated Heart Failure (DAD-HF) trial, based on 50 patients out of a projected enrollment of 300, here at the Heart Failure Society of America 2009 Scientific Meeting.

In his presentation, he pointed to previous studies suggesting that renal function deteriorates in one third to one half of patients hospitalized with ADHF. Intravenous loop diuretics get much of the blame--kidney damage associated with them in ADHF has been associated with increased risk of hospitalization and death.

Dopamine, at dosages lower than those generally used for inotropic effect, improves renal perfusion, decreases aldosterone levels, and raises urine output, observed Triposkiadis, who is one of the trial's principal investigators. In DAD-HF, "low-dose" dopamine means 5 {:mu:}g/kg per min for eight hours.

"There's always been this idea of a renal dose of dopamine in which, at very low doses, its primary effects increased renal blood flow without a lot of inotropy," added Dr G Michael Felker (Duke Clinical Research Institute, Durham, NC) for heartwire .

Used that way, the dosage is usually 2 or 3 {:mu:}g/kg per min, "but if you asked everybody in this room, what is a renal dose of dopamine and what is an inotropic dose, you'd get a wide spread of answers, I think," Felder said. Some of the mainstay drugs in ADHF have been around so long that "they've never been subjected to the same scrutiny that a new drug would [face], so they're used based mostly on expert opinion and just longstanding clinical experience, not data." Furosemide and dopamine are two such examples.

Increasingly, such drugs are belatedly being tested in randomized controlled trials, noted Felker. "It's not very glamorous, but it's important work."

It's a promising strategy that needs to be tested in a larger population.

As the invited commentator on the DAD-HF presentation, Felker said the "striking" preservation of renal function seen with the low-dose dopamine-furosemide combination in the trial, compared with "high-dose" furosemide, was remarkable for a small pilot study. "Even at 24 hours we see a very dramatic difference in renal function."

But the study's dopamine dosage--5 {:mu:}g/kg per min--is high if renal function is the only target, he said. "We're really dealing with both a renal and an inotropic intervention when we give dopamine at this dose."

The double-blind DAD-HF trial is randomizing ADHF patients to receive higher-dose IV furosemide (40 mg bolus followed by 20 mg/hour for 8 hours), or lower-dose furosemide (40 mg bolus followed by 5 mg/hour for eight hours) plus dopamine (5 {:mu:}g/kg per min for eight hours).

Eligibility for the study, underway at seven centers in Greece, Germany, and the US, include a diagnosis of ADHF marked by severe recent-onset dyspnea, congestion, admission arterial blood oxygen <90%, and plasma B-type natriuretic peptide (BNP) levels >400 pg/mL, all in the absence of severe renal failure (serum creatinine >200 {:mu:}mol/L or GFR <30 mL/min per 1.73 m2) or a systolic blood pressure <90 mm Hg.

In the preliminary analysis of the first 50 patients randomized at the centers in Greece, as reported by Triposkiadis, the two patient groups were statistically comparable with respect to the prevalence of hypertension, atrial fibrillation, diabetes, chronic lung disease, and the use of ACE inhibitors or angiotensin-receptor blockers, beta blockers, aldosterone antagonists, digoxin, and statins.

The 25 who received full-dose furosemide and the 25 who received the two drugs a low dosages produced statistically comparable volumes of urine.

Cumulative Urine Output During Eight-Hour Infusion of High-Dose Furosemide vs Low-Dose Furosemide Plus Low-Dose Dopamine*

Hour of infusion High-dose furosemide (mL), n=25 Low-dose furosemide/dopamine (mL), n=25
2 647 847
4 948 1272
6 1223 1510
8 2214 1888
*All differences between the groups nonsignificant.

A 0.6 mEq/mL drop in serum potassium levels from baseline to 24 hours in the high-dose group was significant (p=0.012), and a 0.3 mEq/mL decrease in the low-dose group was not (p=0.09). Hypokalemia (serum potassium <3.5 mEq/L) developed in two patients who received high-dose furosemide but in none who received low-dose furosemide (p=0.013)

The low-dose regimen was associated with significantly less renal damage by several measures.

In the high-dose group, serum creatinine rose significantly from 1.32 mg/dL at baseline to 1.48 mg/dL at 24 hours (p<0.01), but it was more or less stable in the low-dose group, at 1.34 and 1.30 mg/dL, respectively. Blood urea nitrogen (BUN) increased from 43.2 mg/dL at baseline to 51.2 mg/dL at 24 hours (p<0.01) in the high-dose group, but nonsignificantly went from 45.9 to 43.8 mg/dL in the low-dose group.

Measures of Worsening Renal Function at 24 Hours for High-Dose Furosemide vs Low-Dose Furosemide Plus Low-Dose Dopamine

Measure High-dose furosemide (%) Low-dose furosemide/dopamine (%) p
sCr, >0.3 mg/dL increase 36 4 0.005
sCr, >25% increase 36 4 0.004
eGFR, >10% decrease 64 28 0.011

sCr=serum creatinine; eGFR=estimated glomerular filtration rate.

Dyspnea improved significantly and to similar degrees in both groups. There were no significant differences in hospital length of stay or clinical outcomes out to 60 days (the study is looking at mortality and all-cause hospitalization at one year as the primary end point and at 60 days as a secondary end point [2]).

In his formal comments on DAD-HF, Felker brought up a consideration that complicates interpretation of the analysis. Based on the numbers reported by Triposkiadis, the 25 low-dose patients might have had lower blood pressures than the 25 high-dose patients (even though the observed differences fell short of significance), he observed. That could have accounted for at least some of dopamine's apparent renoprotective effect, given that hypertension is a likely risk factor for worsening renal function, he observed.

The mean baseline blood pressures were 153/91 mm Hg in the high-dose group and 135/83 mm Hg in the low-dose group (p=0.065 for systolic and p=0.078 for diastolic pressure).

Dr Randall C Starling (Cleveland Clinic, OH), a lead investigator with DAD-HF and comoderator of the session in which it was presented, who isn't involved in DAD-HF, said to heartwire that despite the small number of patients in this preliminary analysis, low-dose dopamine had a "dramatic" renoprotective effect and "a similar ability to decongest. It's a promising strategy that needs to be tested in a larger population."

Triposkiadis had no disclosures. Felker reports receiving research grants from Amgen and Roche Diagnostics, and being a consultant or on an advisory board for Amgen, Corthera, and XDx. Starling reports receiving research grants from Biotronik and Thoratec and being a consultant or on an advisory board for Medtronic.

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