REVIEW URRENT C OPINION

Is there still a role for low-dose dopamine use in acute heart failure? Isabel Torres-Courchoud a and Horng H. Chen b

Purpose of review Acute heart failure (AHF) is a major health problem worldwide, with no proven therapy. Low-dose dopamine has been used in this entity to improve renal outcomes in the past decades. The aim of this article is to review the former and recent clinical trials about the use of low-dose dopamine in AHF. Recent findings The Dopamine in Acute Decompensated Heart Failure II study enrolled 161 patients with AHF and found no improvement in clinical outcomes with the addition of dopamine. Similarly, the Renal Optimization Strategies Evaluation in Acute Heart Failure trial, which included 360 patients with AHF and renal dysfunction, evaluated the efficacy of 72-h infusion of either low-dose nesiritide or low-dose dopamine versus placebo in addition to standardized diuretic treatment. No differences were found between both treatment groups and placebo with regard to the coprimary endpoints of cumulative urine volume and change from baseline in plasma cystatin C. Summary On the basis of the current data, there is no role for the routine use of low-dose dopamine in nonhypotensive patients with AHF. Further studies are needed to define the role of low-dose dopamine in patients with AHF and hypotension. Until the availability of more data, the use of dopamine in AHF should be individualized. Keywords acute heart failure, cardiorenal syndrome, dopamine, renal dysfunction

INTRODUCTION Acute heart failure (AHF) is a major health problem with dismal clinical outcomes despite current therapies. The concept of low-dose, or ‘renal dose’, dopamine has persisted since the first clinical description of its use in patients with AHF [1]. Low-dose dopamine has been used for decades in patients with AHF, in addition to loop diuretics, to enhance renal blood flow (RBF) and diuresis and preserve renal function. Recent studies have questioned the efficacy of low-dose dopamine in AHF. The purpose of this review is to critically appraise the available studies, especially the results of the most recent randomized clinical trials on this topic.

ACUTE HEART FAILURE AND RENAL DYSFUNCTION Heart failure is a global problem, with over 20 million people affected [2]. The overall prevalence of heart failure in the adult population in industrialized countries is approximately 2% [3].

AHF is a major health problem that is associated with several millions of hospitalizations worldwide each year, poor short-term outcomes and high costs [4,5]. It remains the single most common admitting diagnosis in the United States for patients aged over 65 years [6], accounting for 1 000 000 admissions and more than 6 million hospital days [7]. Renal dysfunction in patients with AHF is common and is increasingly recognized as an independent risk factor for morbidity and mortality [8–12]. Acute kidney injury during AHF, also known as type 1 cardiorenal syndrome, is defined as an increase in plasma a University Clinic Hospital Lozano Blesa, Zaragoza, Spain and bDivision of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota, USA

Correspondence to Horng H. Chen, MB, BCh, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1 507 284 1644; fax: +1 507 266 4710; e-mail: chen. [email protected] Curr Opin Crit Care 2014, 20:467–471 DOI:10.1097/MCC.0000000000000133

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KEY POINTS  Preclinical physiological studies and previous small clinical trials have suggested that low-dose dopamine may have renal-specific actions that enhance RBF and diuresis with renal protective actions.  Recently completed DAD-HF II and ROSE AHF randomized clinical trials do not support the routine use of low-dose dopamine in AHF.  Importantly, these studies also demonstrated that lowdose dopamine is not renal-specific in all patients, as demonstrated by the increased incidence of tachycardia in patients receiving dopamine.  On the basis of the current data, there is no role for the routine use of low-dose dopamine in nonhypotensive patients with AHF.  Further studies are needed to define the role of lowdose dopamine in patients with AHF and hypotension. Until the availability of more data, the use of dopamine in AHF should be individualized.

a2-adrenergic receptors, producing vasoconstriction and an increase of systemic vascular resistance [7,16,23]. Criteria for low, intermediate and highdose dopamine should be considered a general dose guidance, because personal response to dopamine may vary between different people [7,21]. Dopamine is metabolized by monoamine oxidase (MAO) and catechol-o-methyl transferase, and this has been taken into account in patients taking MAO inhibitors at the same time [24]. The adverse events associated with dopamine include nausea, vomiting, headache, and, more importantly, tachycardia, arrhythmias, hypertension and local extravasation, which can cause tissue necrosis.

CONTROVERSIES ABOUT THE RENAL ACTIONS OF LOW-DOSE DOPAMINE Dopamine is often used empirically in critically ill or AHF patients with oliguria or renal dysfunction to improve renal outcomes [25]. The 2013 American Heart Association/American College of Cardiology (AHA/ACC) guidelines [26 ] recommended considering the use of low-dose dopamine, in addition to intravenous diuretics, to improve diuresis and reduce fluid overload when enhancing RBF and function, but acknowledged the lack of data supporting the efficacy of this intervention (grade 2b recommendation, level of evidence B). In the last decade, several studies have investigated the potential renal-protective effects of low-dose dopamine, in addition to diuretic therapy, in critically ill or AHF patients considered at risk for, or with established, renal impairment. Varriale et al. [25] performed a study which included 20 patients with AHF. All patients received a similar dose of loop diuretic (bumetanide 2 mg/day), but 10 of them received additional dopamine infusion at 2 mg/kg/ min. They observed that the dopamine-treated group had a significant improvement in renal function as compared with the diuretic-alone group. A similar study done by Cotter et al. [27] in 20 patients with AHF revealed that the patients who received low-dose dopamine (4 mg/kg/min) in addition to low-dose (80 mg/day) oral furosemide experienced an improvement in renal function, a reduced incidence of hypokalemia and a preservation of mean arterial pressure as compared with patients who received either low-dose dopamine plus high-dose furosemide or patients who received high-dose furosemide alone. Subsequently, Bellomo et al. [28] carried out a study of 328 patients admitted to an ICU with high risk of renal failure (patients with increased creatinine and decreased diuresis), comparing placebo with low-dose dopamine (2 mg/kg/min) to reduce &

creatinine by 0.3 mg/dl [13–15], and/or 25% from baseline. This occurs in 25–30% of patients with AHF [5,16] and can develop in the early postdischarge period [17]. Risk factors include hypertension, diabetes, elderly age and prior history of heart or renal failure [16,18–20]. Hence, there is an unmet need for therapeutic strategies to enhance decongestion while preserving renal function in AHF.

PHYSIOLOGY OF DOPAMINE Dopamine is a natural catecholamine with diverse biological actions on the vasculature. It typically has dose-dependent effects on dopaminergic, b-adrenergic and a-adrenergic receptors [7]. At low doses (< 3 mg/kg/min), dopamine activates the dopaminergic-A1 receptors, producing vasodilatation of the renal, mesenteric, coronary and cerebral vessels. It also stimulates dopaminergic-A2 receptors located on presynaptic terminals of sympathetic postganglionic fibers, producing inhibition of norepinephrine release [7,13]. In the kidney, the effects on dopaminergic A1 and A2 receptors result in increases in RBF and in the glomerular filtration rate (GFR) and promote natriuresis [1,19,21,22]. At intermediate doses, normally between 3 and 5 mg/kg/ min, dopamine activates b1-adrenergic receptors, increasing cardiac output by increasing stroke volume and heart rate due to its inotropic properties, which may be associated with cardiac arrhythmias [5,7,16,23]. At high doses, which are considered as doses higher than 5 mg/kg/min, dopamine activates a1 and 468

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Use of dopamine in acute heart failure Torres-Courchoud and Chen

the development of renal injury. The dose of furosemide used and peak serum creatinine were similar in both groups, with no differences in other clinical markers of renal function. The authors concluded that dopamine did not confer protection from renal dysfunction. These findings are consistent with a systematic review and meta-analysis by Friedrich et al. [1] of 61 trials involving low-dose dopamine with a total of 3359 patients. In this heterogeneous group of studies, dopamine did increase urine output during the first 24 h, but did not alter mortality or the need for dialysis as compared with placebo. On the contrary, Elkayam et al. [21] demonstrated a dose-dependent increase in RBF in chronic heart failure patients receiving dopamine at increasing doses from 2 to 10 mg/kg/min. A retrospective study by Aziz et al. [29], which included 116 patients with AHF, compared patients who received a continuous infusion of furosemide combined with low-dose dopamine (mean dose of 2 mg/kg/min) with those who received intermittent boluses of furosemide alone. Patients who received dopamine were sicker, had worse renal function at baseline, and received lower doses of furosemide as compared with the bolus furosemide group. Despite all that, the patients in the dopamine group had preservation of renal function, higher hourly urine output, and significantly lower admission rates when followed for 30 days. The above studies provided contradictory results regarding the efficacy of low-dose dopamine in preserving renal function. This is due, in part, to the variation in study design, patient population, dose and type of diuretics used as well as the dose and duration of the dopamine infusion.

THE MOST RECENT CLINICAL STUDIES Recently, the Dopamine in Acute Decompensated Heart Failure (DAD-HF) and DAD-HF II clinical trials investigated the use of dopamine in AHF. The DADHF trial [30] included 60 patients with AHF randomized to either high-dose furosemide alone (continued infusion of furosemide at 20 mg/h) or low-dose furosemide (continued infusion of furosemide at 5 mg/h) plus dopamine (5 mg/kg/min) for 8 h. They did not see any difference between the diuresis or the dyspnea score between the two groups. However, the incidence of worsening renal function was higher in the high-dose furosemide group (30%) as compared with the low-dose furosemide plus dopamine group (6.7%). The DAD-HF II trial [31 ] enrolled 161 patients with AHF, randomized to receive: first, high-dose &&

furosemide alone (continued infusion of furosemide at 20 mg/h); second, low-dose furosemide alone (continued infusion of furosemide at 5 mg/h); or, third, low-dose furosemide (continued infusion of furosemide at 5 mg/h) plus dopamine (5 mg/kg/min) for 8 h. There were no significant differences in 60-day and 1-year all-cause mortality rate, hospitalization for heart failure or overall dyspnea relief between the treatment groups. Notably, there was a higher incidence of worsening renal failure in the high-dose furosemide group compared with the other treatment arms. The trial was stopped early because of an increased incidence of tachycardia in the dopamine plus furosemide treatment arm. The dose of dopamine used in both DAD-HF trials (5 mg/kg/min) was at a level at which the inotropic effects of the medication predominate. The Renal Optimization Strategies Evaluation in Acute Heart Failure trial [32 ] included 360 patients with AHF and renal dysfunction (GFR of 15–60 ml/ min/1.73 m2 as estimated by the Modification of Diet in Renal Disease equation) and determined the efficacy of 72 h infusion of either low-dose nesiritide (0.005 mg/kg/min) or dopamine (2 mg/kg/min) on enhancing decongestion when preserving renal function. All patients received intravenous furosemide treatment at 2.5 times the equivalent of oral outpatient dosing for the first 24 h. The primary endpoints were 72-h cumulative urine volume and change in serum cystatin C from enrollment to 72 h as a measurement of renal function preservation. There were no significant differences in either the coprimary endpoints of 72-h cumulative urine volume or the change in cystatin C from baseline to 72 h when comparing low-dose dopamine with placebo. Furthermore, there were no significant differences between the groups in other secondary endpoints assessing for decongestion or renal function. At 60 days, there were also no significant differences between the dopamine group and placebo in terms of death, serious adverse events and heart failure-related visits or hospitalization. There were also no significant differences in mortality between the dopamine group and placebo at 180 days. However, dopamine-treated patients were more likely to have the study drug discontinued because of tachycardia. Subgroup analyses suggested a trend for differential treatment effects according to the ejection fraction. The 72-h cumulative urine volume tended to be lower with low-dose dopamine as compared with placebo in subgroups of patients with higher ejection fraction. Overall, the study demonstrated that, in patients with AHF and moderate-to-severe renal dysfunction, low-dose dopamine did not enhance decongestion or improve

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renal function when used in conjunction with a standard diuretic.

REFERENCES AND RECOMMENDED READING

SUMMARY AND CONCLUSION

Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest

Preclinical physiological studies and previous small clinical trials have suggested that low-dose dopamine may have renal-specific actions that enhance RBF and diuresis with renal-protective actions. However, recently completed randomized clinical trials do not support the routine use of lowdose dopamine in AHF. Importantly, these studies also demonstrated that low-dose dopamine is not renal-specific in all patients, as demonstrated by the increased incidence of tachycardia in patients receiving dopamine. Hence, is there a role for low-dose dopamine in the management of AHF? It has been demonstrated that dopamine is effective in raising blood pressure (BP) in hypotensive shock [33,34]. The 2013 American College of Cardiology Foundation (ACCF)/AHA guideline [26 ] for the management of heart failure provides the following level IIb recommendation: shortterm, continuous intravenous inotropic support may be reasonable for hospitalized patients presenting with documented severe systolic dysfunction, low BP and significantly depressed cardiac output to maintain systemic perfusion and to preserve endorgan performance [3,35,36]. Hence, dopamine could be used in patients with hypotensive AHF, in whom we were not able to increase diuretic dose or to use a vasodilator due to low BP [37], to increase BP and improve the hemodynamic situation, with the minimal dopamine dose to avoid adverse events. In conclusion, on the basis of the current data, there is no role for the routine use of low-dose dopamine in nonhypotensive patients with AHF. Further studies are needed to define the role of low-dose dopamine in patients with AHF and hypotension. Until the availability of more data, the use of dopamine in AHF should be individualized. &

Acknowledgements None. Conflicts of interest Dr Chen has received Research Grants from NIH; Scios Inc; Mayo Clinic and has filed patents for chimeric natriuretic peptides; Mayo Clinic has licensed patents to Nile Therapeutics and Anexon with other patents pending at the US patent office; Dr Chen has received royalties from Nile Therapeutics, Anexon Inc. and UpToDate; and is the co-founder of Zumbro Discovery Inc. 470

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Is there still a role for low-dose dopamine use in acute heart failure?

Acute heart failure (AHF) is a major health problem worldwide, with no proven therapy. Low-dose dopamine has been used in this entity to improve renal...
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