Avoid Low-Dose Dopamine, Prefer Bolus Furosemide in Preserved-EF Acute HF: ROPA-DOP

September 22, 2017

GRAPEVINE, TX — With low-dose dopamine sometimes used in acute decompensated heart failure (ADHF) without much clinical-trial support, there's now a larger evidence base arguing against it, especially in patients with heart failure and preserved ejection fraction (HFpEF).

In a small trial randomizing such patients to receive or not receive low-dose dopamine and separately to either bolus-dosed or continuously infused furosemide, dopamine showed no significant effect on renal function or diuresis. And the continuously infused diuretic seemed to harm compared with bolus dosing.

Both findings from the Randomized Evaluation of HFpEF Patients With Acute Heart Failure and Dopamine (ROPA-DOP) trial build on earlier, limited ADHF trial evidence in both HFpEF and HF with reduced ejection fraction (HFrEF).

In fact, interpretation of the trial, an especially rare one in HFpEF, depends a lot on how it fits with such trials as ROSE-AHF (which post hoc had a HFpEF subgroup), DAD-HF, and DOSE, judging from the presentation of ROPA-DOP by Dr Kavita Sharma (Johns Hopkins University, Baltimore, MD), here at the Heart Failure Society of America 2017 Scientific Meeting, as well as other experts who heard the results.

"It's clearly a neutral trial result, and while there is no harm from dopamine, which what was suggested in the ROSE-AHF study in HFpEF, there was clearly no benefit in the overall cohort," although results in some subgroups in ROPA-DOP are currently being explored, Sharma told theheart.org | Medscape Cardiology.

"Overall, I think it speaks pretty clearly that in HFpEF and HFrEF, there's no compelling data to support low-dose dopamine in the overall patient population."

In a big caveat, ROPA-DOP randomized only 90 patients at one center, although it initially had a projected enrollment of about 120. Sharma said enrollment was slow and was halted early due to concerns about "feasibility."

Low-dose dopamine in ADHF is occasionally added to IV diuretics to potentiate their effect and possibly to protect the kidneys, with some evidence suggesting they improve decongestion. But that's based mostly on surrogate end points and not in randomized trials, said Dr Christopher M O'Connor (Inova Heart & Vascular Institute, Falls Church, VA) in an interview.

So low-dose dopamine is sometimes used in ADHF, but not widely, according to O'Connor, who was not involved in ROPA-DOP. It should be investigated further in larger trials with clinical end points, but "I would say, hold back on using it until more data are in."

ROPA-DOP is "an important trial" for showing that dopamine didn't significantly affect renal function or health or volume output, said Prof Gerasimos Filippatos (Athens University Hospital, Greece) as a formal discussant following Sharma's presentation of the trial.

That, Filippatos pointed out, contrasts with the limited prior evidence in HFpEF. A post hoc analysis of the 2013 ROSE-AHF trial suggested that, in contrast to the neutral effect of low-dose dopamine in its overall population with ADHF, in the subgroup with HFpEF dopamine was associated with significantly lower fluid-volume and sodium output as well as greater mortality at 6 months and death or HF hospitalization at 2 months[1].

The investigator-blinded, 2x2 randomization scheme in ROPA-DOP assigned 90 patients with preserved-EF ADHF to receive furosemide either as a bolus or continuous infusion, with vs without dopamine at 3 µg/kg/min, over 72 hours.

To be eligible for the trial, patients were required to have an LVEF of at least 50% and an estimated GFR >15 mL/min/1.73 m2. As might not be surprising in a HFpEF trial, 61% of the population were women. Their mean BMI was 40.8, and more than half in each assigned group were African American.

Low-Dose Dopamine, Use vs Nonuse, in Preserved-EF ADHF at 72 Hours in ROPA-DOP

Parameters No dopamine Low-dose dopamine Unadjusted P Adjusted P*
Increase in creatinine (%) 8.0 12.8 0.33 0.34
Worsening renal function (%)** 23.8 25.0 0.89 0.87
Volume output (mL) 10,340 10,705 0.67 0.42

*Linear regression analysis adjusted for age, sex, race, BMI, smoking, HTN, diabetes, atrial fibrillation, baseline GFR, and systolic BP, heart rate, and fluid balance changes at 72 hours.

**Based on change in glomerular filtration rate.

The trial's exploration of whether to give furosemide as a twice-daily bolus or continuous infusion followed the 308-patient DOSE trial's finding of parity between the two strategies for both renal function and symptom relief. In practice, Sharma observed, bolus furosemide is often the first choice, and a continuous infusion can be tried if the first method doesn't work well.

But in an adjusted analysis, ROPA-DOP saw significantly more worsening renal function with the continuous diuretic-infusion strategy, which therefore should be avoided, at least in patients with acute HFpEF, Sharma said in an interview.

Furosemide, Continuous vs Intermittent Bolus, in Preserved-EF ADHF at 72 Hours in ROPA-DOP

Parameters Intermittent bolus Continuous infusion Unadjusted P Adjusted P*
Increase in creatinine (%) 4.6 16.0 0.02 0.03
Worsening renal function (%)** 11.6 36.2 <0.01 0.02
Volume output (mL) 10,300 10,749 0.61 0.98

*Linear regression analysis adjusted for age, sex, race, BMI, smoking, HTN, diabetes, atrial fibrillation, baseline GFR, and systolic BP, heart rate, and fluid balance changes at 72 hours.

**Based on change in glomerular filtration rate.

"In a disease where we really have no clear guidelines as to how to manage patients in the acute setting, I certainly think you'd think twice before using continuous Lasix for diuresis," said Sharma, using the iconic commercial name for furosemide.

Several observers questioned whether much should be made of the trial's use of serum creatinine changes as an outcomes measure.

"We know that worsening renal function and increasing creatinine, without the finding of congestion, is not as important as we thought anymore," according to Filippatos. More prognostically important, he said, may be renal function at baseline as well as the duration of worsening renal function.

"A change in creatinine at 72 hours is not going to really tell you the whole picture," agreed O'Connor when interviewed. "Really getting at a full understanding of how the patient performs through the hospitalization would be much more important."

Anecdotally, said Sharma, acute HFpEF patients with right ventricular failure may represent a subgroup that might respond to dopamine. "We will do due diligence to look at this particular subgroup that we think may have a signal, but the numbers of course will be limited." Based on the trial as a whole, however, "it's really hard to support the continued use of dopamine."

Sharma and Filippatos had no relevant financial relationships. O'Connor discloses consulting or being on an advisory board for ResMed, Merck, Bristol-Meyer Squibb, Actelion, ARCA, and Bayer.

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