Comparison of dobutamine versus milrinone therapy in hospitalized patients awaiting cardiac transplantation: A prospective, randomized trial

Surgery

Comparison of dobutamine versus milrinone therapy in hospitalized patients awaiting cardiac transplantation: A prospective, randomized trial Juan M. Aranda, Jr, MD, Richard S. Schofield, MD, Daniel F. Pauly, MD, PhD, Timothy S. Cleeton, ARNP, Tracy C. Walker, ARNP, V. Steven Monroe, Jr, MD, Dana Leach, RN, Larry M. Lopez, Pharm D, and James A. Hill, MD, MS Gainesville, Fla

Background The use of dobutamine or milrinone for inotropic support in patients with heart failure awaiting cardiac transplantation is largely arbitrary and based on institutional preference. The costs and effectiveness of these drugs have yet to be compared in a prospective, randomized study. Methods We compared clinical outcomes and costs associated with the use of dobutamine or milrinone in 36 hospitalized patients awaiting cardiac transplantation. Patients were randomly assigned to receive either dobutamine or milrinone at the time of initial hospitalization and were followed until death, transplantation, or placement of mechanical cardiac support (intra-aortic balloon pump or left ventricular assist device).

Results Seventeen patients were randomly assigned to receive dobutamine (mean dose 4.1 ⫾ 1.4 ␮g/kg/min) and 19 patients received milrinone (mean dose 0.39 ⫾ 1.0 ␮g/kg/min). Therapy lasted 50 ⫾ 46 days for those in the dobutamine group and 63 ⫾ 45 days in the milrinone group. We did not detect differences between the 2 groups in right heart hemodynamics, death, need for additional vasodilator/inotropic therapy, or need for mechanical cardiac support before transplantation. Ventricular arrhythmias requiring increased antiarrhythmic therapy occurred frequently in both groups. Total acquisition cost of milrinone was significantly higher than that of dobutamine ($16,270 ⫾ 1334 vs $380 ⫾ 533 P ⬍ .00001).

Conclusions Both dobutamine and milrinone can be used successfully as pharmacologic therapy for a bridge to heart transplantation. Despite similar clinical outcomes, treatment with milrinone incurs greater cost. (Am Heart J 2003; 145:324-9.)

See related Editorial on page 198.

The availability of donor organs for heart transplantation is limited, and a long list of potential recipients has accumulated. As a consequence, these patients are frequently required to undergo prolonged infusions of inotropic drugs as a chemical bridge to heart transplantation. Catecholamines (eg, dobutamine) and phosphodiestease inhibitors (eg, milrinone) have been used for inotropic support in hospitalized patients awaiting

From the University of Florida College of Medicine, Division of Cardiovascular Medicine, the University of Florida Shands Transplant Center, and the University of Florida College of Pharmacy Clinical Pharmacy Program, Gainesville, Fla. Submitted October 1, 2001; accepted May 3, 2002. Reprint requests: Juan M. Aranda, Jr, MD, University of Florida College of Medicine, Heart Transplant/Heart Failure Program, 1600 SW Archer Rd, Room 10-539, Gainesville, FL 32610-0395. E-mail: [email protected] Copyright 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1067/mhj.2003.50

heart transplantation. These drugs have clinically similar effects in patients with severe heart failure, although important physiologic and hemodynamic differences have been described.1-3 Criteria for the use of either agent vary widely among institutions, with some favoring dobutamine because of cost concerns and others preferring milrinone because of fewer arrhythmias and better hemodynamic profile. Clinical trials investigating the longterm use of either agent have been limited and are largely observational.1-3 The conflicting physiologic interactions of dobutamine (a ␤-receptor agonist) and ␤-receptor blockers, which are known to have significant benefits in congestive heart failure, make the use of milrinone attractive.4-6 Thus, a combination of inotropic support with intravenous milrinone and concurrent ␤-receptor blockade is physiologically appealing in these patients with end-stage disease.7 To date, there have been no prospective, randomized trials comparing clinical effectiveness of milrinone versus

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dobutamine in patients awaiting heart transplantation. In addition, the significant cost differential between these agents warrants careful consideration of the clinical need for one agent over another. In this prospective, randomized investigation, we sought to evaluate the cost and clinical outcomes associated with longterm dobutamine or milrinone infusion as a bridge to heart transplantation in hospitalized patients.

Methods Patients for this study were recruited from the adult cardiac transplant waiting list at the Shands Transplant Center at the University of Florida. The criteria for entry into the study included age ⬎18 years, prior approval for cardiac transplantation, and exacerbation of heart failure not only necessitating hospitalization but demonstrating inotropic dependency. Inotropic dependency was defined as ⬎2 admissions for decompensated heart failure requiring inotropes from the time of referral to our institution or severe pulmonary hypertension requiring inotropic therapy to maintain adequate pulmonary vascular resistance acceptable for heart transplantation. Exclusion criteria included any history of intolerance to either dobutamine or milrinone, hemodynamic instability at the time of random assignment requiring mechanical cardiac support (intra-aortic balloon pump or left ventricular assist device placement), normal left ventricular filling pressures (defined as mean pulmonary capillary wedge pressure [PCWP] ⬍15 mm Hg), and development of noncardiac medical illness sufficient to remove patients from the cardiac transplant waiting list. On admission to the hospital, patients gave informed consent to participate in the study, as approved by the local institutional review board. Patients were then randomly assigned to receive either dobutamine or milrinone infusions in an unblinded fashion. Milrinone was infused without a loading dose at an initial infusion rate of 0.25 ␮g/kg per minute and titrated to desired clinical effects in 0.125-␮g/kg per minute increments to a maximum dose of 0.75 ␮g/kg per minute. Dobutamine was infused at a starting dose of 2.5 ␮g/kg per minute and titrated in 2.5-␮g/kg per minute increments to a maximum dose of 10 ␮g/kg per minute. Criteria for uptitration of either drug included persistence of New York Heart Association class III or IV symptoms, persistent pulmonary vascular resistance ⬎3 Wood units, or persistent mean PCWP ⬎20 mm Hg. All patients underwent continuous telemetry monitoring and periodic right heart catheterization to evaluate right heart pressures and pulmonary vascular resistance. Cost data for milrinone and dobutamine were retrieved from the hospital pharmacy database. Primary end points of the analysis included hemodynamic decompensation (assessed by periodic right heart catheterization), occurrence of ventricular arrhythmias requiring increased antiarrhythmic therapy, and need for additional vasodilator or inotropic therapy (nitroprusside or dopamine). Secondary end points included death, need for mechanical cardiac support, heart transplantation, and need to add or cross over to the alternative inotropic agent.

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Table I. Baseline demographics of patients awaiting heart transplantation Dobutamine Milrinone (n ⴝ 19) (n ⴝ 17) Age (y) Sex (%) Male Female Race (%) White African American Etiology of congestive heart failure (%) Ischemic Nonischemic Mean dose (␮g/kg/min)

P

54 ⫾ 9

61 ⫾ 8

.01

17 (89) 2 (11)

10 (59) 7 (41)

.045

18 (95) 1 (5)

16 (94) 1 (6)

.73

9 (47) 10 (53) 4.1 ⫾ 1.4

11 (65) .24 6 (35) 0.39 ⫾ 0.13

Statistical analysis Primary outcome variables were compared between treatment groups by use of the independent-sample t test. Analysis of covariance was used for similar comparisons while adjusting for relevant confounding variables. Between-group frequency of occurrence and secondary end points was compared by means of the Fisher exact test. The Student t test for paired and unpaired observations was used to compare within-patient and between-group changes in hemodynamic parameters, respectively. In all instances, observed differences were considered significant if the associated P value was ⱕ.05. Sample-size calculation was determined regarding changes in PCWP. Specifically, we assumed that PCWP on therapy would range from 10 to 25 mm Hg, with an associated standard deviation of 3.75. We sought to detect, with 95% confidence, a difference between the groups of ⫾2 mm Hg. Our sample size estimate with the use of these assumptions and n ⫽ (Z/␦)2, where Z ⫽ 1.96 and ␦ ⫽ 2/3.75 or 0.53, was 14 subjects in each group. The actual power of our observations is 0.7. Because age and sex distribution (the only baseline demographics that were different between the groups) were not included in these power calculations, we assume that the observed differences in these baseline demographics occurred as a result of chance.

Results From January 1999 to May 2000, 36 patients listed as United Network Organ Sharing status 1B were randomly assigned to receive dobutamine (n ⫽ 17) or milrinone (n ⫽ 19). Baseline characteristics of these patients are summarized in Table I. There were more male patients in the dobutamine group, whereas patients receiving milrinone tended to be older. There was no difference in race or underlying cause of heart failure between the dobutamine and milrinone groups. The average dose of dobutamine was 4.1 ⫾ 1.4 ␮g/kg per minute; the average dose of milrinone was 0.39 ⫾ 0.10 ␮g/kg per minute.

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Table II. Outcomes of patients randomized to dobutamine or milrinone Milrinone Dobutamine (n ⴝ 19) (n ⴝ 17) P Heart transplant (%) 16 (84) Inotrope (bridge to heart transplant) 12 (63) Left ventricular assist device (bridge to 1 (5) heart transplant) Intra-aortic balloon pump (bridge to 1 (5) heart transplant) Switched to alternate drug 2 (11) Required dopamine* 6 (32) Required nitroprusside* 0 (0) Death (%) 1 (5) Discharge from hospital (%) 2 (11) Length of stay (days) 50 ⫾ 46

16 (94) 12 (71) 1 (6)

.4 .45 .73

1 (5)

.73

2 (12) 3 (18) 3 (18) 0 (0) 1 (6) 63 ⫾ 45

.65 .28 .09 .53 .54 .38

*Need for second inotropic or vasodilator agent.

Of the 36 patients randomly assigned to receive dobutamine or milrinone, 32 underwent heart transplantation (16 milrinone vs 16 dobutamine) (Table II). Twenty-four patients underwent transplantation with their initial randomized inotropic agent as a bridge to transplantation (12 milrinone vs 12 dobutamine). Two patients required a left ventricular assist device as a bridge to heart transplantation (1 milrinone vs 1 dobutamine), whereas 2 patients required an intra-aortic balloon pump (1 milrinone vs 1 dobutamine). Four patients (2 milrinone vs 2 dobutamine) required crossing over to the alternative therapy because of arrhythmias (2 dobutamine) and hypotension (2 milrinone). Pretransplantation mortality rate while awaiting heart transplantation was 3%: one patient on milrinone had cardiac arrest due to myocardial infarction. Three patients (2 milrinone vs 1 dobutamine) improved on inotropic therapy and were subsequently discharged from the hospital. There was no difference in outcomes such as heart transplantation, left ventricular assist device, intra-aortic balloon pump, death, or improvement on inotropic therapy between the 2 groups. Baseline and follow-up hemodynamic pressures at the time of heart transplantation, death, or need for left ventricular assist device are shown in Table III. This patient population had moderate-to-severe pulmonary hypertension before initiation of inotropic therapy (systolic pulmonary artery pressure 44 ⫾ 16 mm Hg milrinone vs 47 ⫾ 13 mm Hg dobutamine). No significant differences were observed in pulmonary pressures or pulmonary vascular resistance at baseline or in association with therapy with either dobutamine or milrinone. The need for a second inotrope (dopamine) or intravenous vasodilator therapy (nitroprusside) to achieve the above hemodynamic response was similar between both groups (Table II).

Subgroup analysis of medication profiles was performed to evaluate the use of ␤-blocker therapy between both groups. Seven patients randomly assigned to dobutamine versus 14 patients randomly assigned to milrinone were receiving ␤-blocker therapy (P ⫽ .0504). The average dose of dobutamine in patients taking ␤-blockers was 3.1 ⫾ 1.0 ␮g/kg per minute, compared with 4.9 ⫾ 1.2 ␮g/kg per minute in patients who were not receiving ␤-blockers (P ⫽ .005). The effect of ␤-blocker therapy on hemodynamic pressure in patients randomly assigned to dobutamine is shown in Table IV. Patients receiving dobutamine with no ␤-blocker therapy had improved trends in hemodynamics compared with patients receiving both dobutamine and ␤-blocker therapy. However, only reduction in mean pulmonary artery pressure in the non–␤-blocker therapy group was significant. The frequency of symptomatic sustained or nonsustained arrhythmias requiring additional antiarrhythmic therapy was analyzed between both groups. Nine patients in each group had ventricular arrhythmia requiring increased antiarrhythmic therapy (P ⫽ .5). Two patients in the dobutamine group required change in inotropic therapy to milrinone because of persistent sustained supraventricular and ventricular tachycardia, respectively. Cost analysis of inotropic treatment was performed on both groups. Despite similar length of stay in both groups (50 ⫾ 46 days dobutamine vs 63 ⫾ 45 days milrinone, P ⫽ .38), milrinone was associated with greater total acquisition cost at heart transplantation compared with dobutamine ($16,227 ⫾ $1334 vs $380 ⫾ $533, respectively, P ⬍ .00001).

Discussion Despite the absence of randomized trials comparing dobutamine with milrinone in patients awaiting heart transplantation, many transplant clinicians use milrinone as initial inotropic therapy in these patients. Observations from this prospective, randomized trial suggest that either dobutamine or milrinone can be used successfully as pharmacologic therapy for a bridge to heart transplantation. Small, systematic, observational reviews have suggested that milrinone used as an initial inotropic agent may be associated with improved outcomes at the time of heart transplantation. Mehra et al8 reported that compared with dobutamine, patients receiving milrinone were less likely to need mechanical ventricular support or intra-aortic balloon pump as a bridge to heart transplantation. Nevertheless, mortality rates while awaiting transplantation were statistically similar in both groups. Other preliminary retrospective data are not consistent with our observations. Higgenbotham et al9 simi-

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Table III. Baseline and follow-up hemodynamic measurements in patients with heart failure randomized to dobutamine or milrinone Milrinone (n ⴝ 19) At baseline Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Systolic pulmonary artery pressure (mm Hg) Diastolic pulmonary artery pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Mean pulmonary capillary wedge pressure (mm Hg) Pulmonary vascular resistance (Wood units) Cardiac output (mL/min) Change at heart transplant Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Systolic pulmonary artery pressure (mm Hg) Diastolic pulmonary artery pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Pulmonary capillary wedge pressure (mm Hg) Pulmonary vascular resistance (Wood units) Cardiac output (mL/min)

Dobutamine (n ⴝ 17)

P

80 ⫾ 16 99 ⫾ 16 61 ⫾ 11 44 ⫾ 16 23 ⫾ 9 29 ⫾ 10 21 ⫾ 9 3.6 ⫾ 2.1 3.2 ⫾ 1.0

74 ⫾ 11 101 ⫾ 13 62 ⫾ 7 47 ⫾ 13 21 ⫾ 12 33 ⫾ 10 21 ⫾ 9 3.7 ⫾ 1.9 3.5 ⫾ 1.4

.27 .72 .81 .58 .44 .42 .29 .93 .75

–8 ⫾ 17 –11 ⫾ 22 67 ⫾ 14 –1.8 ⫾ 11.3 –1.2 ⫾ 7.3 –2.9 ⫾ 7.4 –1.5 ⫾ 4.7 –0.7 ⫾ 2.9 4.2 ⫾ 0.9

–0.1 ⫾ 10 1.5 ⫾ 22 64 ⫾ 9 –6.9 ⫾ 16.6 –1.8 ⫾ 11.9 –7.2 ⫾ 4.5 –5.0 ⫾ 10.9 –1.2 ⫾ 2.6 3.8 ⫾ 1.6

.19 .22 .41 .4 .88 .35 .34 .68 .48

Table IV. Effects of ␤-blocker therapy on hemodynamic pressures in patients randomized to dobutamine

At baseline Systolic pulmonary artery pressure (mm Hg) Diastolic pulmonary artery pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Mean pulmonary capillary wedge pressure (mm Hg) Pulmonary vascular resistance (Wood units) Cardiac output (mL/min) Change at heart transplant Systolic pulmonary artery pressure (mm Hg) Diastolic pulmonary artery pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Mean pulmonary capillary wedge pressure (mm Hg) Pulmonary vascular resistance (Wood units) Cardiac output (mL/min)

larly investigated clinical outcomes in 120 patients admitted for inotropic drug support before heart transplantation. Their retrospective analysis showed that 50% of 66 dobutamine-treated patients were successfully bridged to transplantation compared with 80% of 54 milrinone-treated patients. The patients receiving milrinone had a lower mortality rate on the heart transplantation list, and the hemodynamic measurements within 18 days improved more with milrinone than with dobutamine. Pharmacologic and hemodynamic differences between dobutamine and milrinone are well documented. Monrad et al10 studied the comparative effects

␤-Blocker (n ⴝ 7)

No ␤-blocker (n ⴝ 10)

P

51 ⫾ 12 23 ⫾ 9 37 ⫾ 7 24 ⫾ 8 4⫾2 3.3 ⫾ 1

44 ⫾ 15 21 ⫾ 6 27 ⫾ 8 16 ⫾ 8 3⫾1 4.4 ⫾ 2

.56 .66 .18 .27 .15 .42

–2 ⫾ 11 1⫾4 2⫾4 5⫾5 –0.5 ⫾ 0.4 0.3 ⫾ 0.9

–10 ⫾ 18 –4 ⫾ 14 –12 ⫾ 12 –7 ⫾ 12 –2 ⫾ 3 0.2 ⫾ 1

.46 .46 .03 .06 .31 .94

of milrinone, dobutamine, and nitroprusside on hemodynamics and myocardial energetics in patients with severe congestive heart failure. Compared with milrinone or nitroprusside, dobutamine increased cardiac output, but its use was associated with a smaller reduction in PCWP and significant increases in heart rate and myocardial consumption. Such increases in heart rate and myocardial oxygen consumption are likely to be detrimental in patients with ischemic heart disease.11 The use of milrinone has been associated with a similar or greater reduction in right atrial pressure, left ventricular end-diastolic pressure, systemic vascular resistance, and increased dP/dt when compared

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with dobutamine and nitroprusside in patients with severe congestive heart failure.12,13 The improved early hemodynamic profile seen with milrinone is due to its potent vasodilator and lusitropic activity with minimal effect on heart rate and myocardial consumption.14 Its mechanism of action is independent of ␤-receptor function, with no dependence on downregulation of ␤-adrenergic receptors. Thus, this inotropic agent is attractive in this age of widespread use of ␤-blockers in patients with heart failure. Our study revealed that at the end of almost 2 months of inotropic therapy, the hemodynamic profiles of patients receiving dobutamine and milrinone are similar. This study was not designed to assess how rapidly a hemodynamic response is achieved with one inotropic agent or another. During the pretransplantation period, each patient received aggressive tailored therapy with diuretics and other agents.15 Inotropes are one of many agents that can be used in combination with other medications to achieve optimal hemodynamics and improvement of symptoms. These results suggest that regardless of inotrope therapy used in combination with tailored therapy, the final hemodynamic profile and outcome at heart transplantation are similar. The use of any inotropic agent carries the risk of aggravating ventricular arrhythmias. In this study, ⬎50% of patients in both groups had an increased frequency of ventricular arrhythmias. Although both dobutamine and milrinone tend to exacerbate atrial or ventricular arrhythmia,16 there has been no prospective comparison of these 2 agents regarding arrhythmias. Some studies assessing the safety of milrinone infusion have reported that patients receiving milrinone have low rates of ventricular arrhythmia when compared with patients receiving dobutamine.17,18 The use of a ␤-agonist as inotropic support in the presence of ␤-blocker therapy appears to be counterproductive.19 Reports suggest that in the presence of ␤-blockade, the hemodynamic and clinical effects of dobutamine are blunted.7 Tsvetkova et al7 evaluated the hemodynamic effects of a single infusion of either milrinone or dobutamine in 20 patients receiving chronic carvedilol therapy. Overall, both milrinone and dobutamine produced dose-related increases in cardiac index; however, milrinone produced these effects at standard doses, whereas similar effects with dobutamine were observed only at higher doses (15-20 ␮g/ kg/min). Several small studies reported in abstract form have evaluated the concomitant use of intermittent or continuous milrinone infusions and carvedilol.20-24 The overall conclusion of these studies is that the use of milrinone during titration or maintenance of carvedilol therapy has been associated with use of a larger carvedilol maintenance dose, improved hemodynamic profile, and improved functional class.

In this study, there was a nonstatistical difference in the use of ␤-blocker therapy between the dobutamine and milrinone groups. Forty-one percent of patients receiving dobutamine were receiving ␤-blocker therapy compared with 74% of patients receiving milrinone therapy (P ⫽ .0504). This difference occurred by chance, as the patients in this study were randomly assigned prospectively. Although 41% of patients taking dobutamine were receiving ␤-blockade, there was no difference in outcome between groups. Our data conflict with previous reports of an increased dose of dobutamine necessary to achieve a desired effect in the presence of ␤-blockade. In this study, patients receiving ␤-blockade were taking lower doses of dobutamine than patients not receiving ␤-blocker therapy. Perhaps the issue is not one of a blunted response to dobutamine in the presence of ␤-blockade but one of upregulation of ␤-receptors that allows for a lower dose of dobutamine to achieve a desired effect. We can only speculate on outcomes if a higher number of patients taking dobutamine had been receiving ␤-blockade. Thus, the question of whether ␤-blockade blunts the effect of dobutamine remains unanswered. Finally, our study reveals a considerable cost differential associated with selection of inotropic therapy. The greater acquisition cost of milrinone multiplied by long waiting times amounts to large differences in cost. If outcomes at transplantation are the same, as our observations suggest, then the less expensive agent should be initiated first. The limitation of this study is that it is nonblinded and that various investigators may have significant differences of opinion about the benefit of one drug versus another that potentially alter crossover and need for other support. This prospective trial, although it involves a small number of patients, illustrates the need of a large, prospective, randomized trial to answer the question regarding choice of inotropic agent as a bridge to heart transplantation.

Conclusions The selection of an inotropic agent as a pharmacologic bridge to transplantion is not a simple one. Both dobutamine and milrinone have distinct advantages and disadvantages. These observations suggest that either agent can be used as a bridge to transplantation with similar outcomes. Both dobutamine and milrinone are associated with significant increase in frequency of arrhythmias, whereas use of milrinone is associated with considerably greater cost. Clinical judgment is needed to select the appropriate inotrope on a patientby-patient basis. The authors thank Melanie Fridl Ross, MSJ, ELS, for editorial assistance, and Lisa A. Hamilton, MA, for manuscript preparation.

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