ORIGINAL CONTRIBUTION

Levosimendan vs Dobutamine for Patients With Acute Decompensated Heart Failure

The SURVIVE Randomized Trial
Alexandre Mebazaa, MD, PhD Markku S. Nieminen, MD, PhD Milton Packer, MD Alain Cohen-Solal, MD, PhD Franz X. Kleber, MD Stuart J. Pocock, PhD Roopal Thakkar, MD Robert J. Padley, MD Pentti Po der, MD, PhD Matti Kivikko, MD, PhD for the SURVIVE Investigators
Context Because acute decompensated heart failure causes substantial morbidity and mortality, there is a need for agents that at least improve hemodynamics and relieve symptoms without adversely affecting survival. Objective To assess the effect of a short-term intravenous infusion of levosimendan or dobutamine on long-term survival. Design, Setting, and Patients The Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) study was a randomized, doubleblind trial comparing the efficacy and safety of intravenous levosimendan or dobutamine in 1327 patients hospitalized with acute decompensated heart failure who required inotropic support. The trial was conducted at 75 centers in 9 countries and patients were randomized between March 2003 and December 2004. Interventions Intravenous levosimendan (n = 664) or intravenous dobutamine (n=663). Main Outcome Measure All-cause mortality at 180 days. Results All-cause mortality at 180 days occurred in 173 (26%) patients in the levosimendan group and 185 (28%) patients in the dobutamine group (hazard ratio, 0.91; 95% confidence interval, 0.74-1.13; P =.40). The levosimendan group had greater decreases in B-type natriuretic peptide level at 24 hours that persisted through 5 days compared with the dobutamine group (P.001 for all time points). There were no statistical differences between treatment groups for the other secondary end points (all-cause mortality at 31 days, number of days alive and out of the hospital, patient global assessment, patient assessment of dyspnea at 24 hours, and cardiovascular mortality at 180 days). There was a higher incidence of cardiac failure in the dobutamine group. There were higher incidences of atrial fibrillation, hypokalemia, and headache in the levosimendan group. Conclusion Despite an initial reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes. Trial Registration clinicaltrials.gov Identifier: NCT00348504
JAMA. 2007;297:1883-1891 Author Affiliations: Departments of Anesthesiology (Dr Mebazaa), Critical Care Medicine (Dr Mebazaa), and Cardiology (Dr Cohen-Solal), Universite Paris Diderot and Hospital Lariboisire AP-HP, Paris, France; Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland (Dr Nieminen); Department of Clinical Sciences, University of Texas Southwestern Medical School, Dallas (Dr Packer); Department of Internal Medicine, Charite Medical School, Berlin, Germany (Dr Kleber); Medical Statistics Unit, London School of Hygiene www.jama.com and Tropical Medicine, London, England (Dr Pocock); Cardiovascular Clinical Research, Abbott Laboratories, Abbott Park, Ill (Drs Thakkar and Padley); and Cardiology Unit, Clinical Research and Development, Orion Pharma, Espoo, Finland (Drs Po der and Kivikko). The SURVIVE Investigatiors are listed at the end of this article. Corresponding Author: Alexandre Mebazaa, MD, PhD, Hospital Lariboisire, 2 Rue A Pare , Paris, France 75475 Cedex 10 (alexandre.mebazaa@lrb.aphp.fr).

failure (ADHF) remains a common cause of hospitalization worldwide but it is not clear how patients admitted for clinical deterioration should be managed. Patients are generally treated with diuretics and vasodilators, while patients with evidence of peripheral hypoperfusion also may receive positive inotropes, usually dobutamine or milrinone. These positive inotropic agents improve hemodynamics and symptoms by increasing intracellular cyclic adenosine monophosphate within the failing heart but have been associated with an increased risk of death and other cardiovascular events.1,2 Levosimendan is a pharmacological agent that exerts positive inotropic effects by binding to cardiac troponin C in a calcium-dependent manner, sensitizing myofilaments to calcium.3,4 Levosimendan also has vasodilatory proper-

CUTE DECOMPENSATED HEART

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LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE

Figure 1. Participant Flow Through the Study

1337 Assessed for Eligibility

10 Excluded (Did Not Meet Inclusion or Met Exclusion Criteria)

1327 Randomized

664 Randomized to Receive Levosimendan 660 Received Levosimendan as Assigned

663 Randomized to Receive Dobutamine 660 Received Dobutamine as Assigned

Exclusion criteria included severe ventricular outflow obstruction; systolic blood pressure persistently lower than 85 mm Hg or heart rate persistently at 130/min or higher; intravenous inotrope use during the index hospitalization (except dopamine 2 g/kg per minute or digitalis); history of torsade de pointes; and serum creatinine level higher than 5.1 mg/dL (450 mol/L) or dialysis.
Study Plan

3 Lost to Follow-up 30 Discontinued Intervention 10 Major Cardiovascular Event 9 Serious Adverse Event 9 Event Judged by Investigator to Warrant Withdrawal 2 Other

8 Lost to Follow-up 41 Discontinued Intervention 15 Major Cardiovascular Event 9 Serious Adverse Event 14 Event Judged by Investigator to Warrant Withdrawal 3 Other

664 Included in Primary Efficacy Analysis 660 Included in Safety Analysis 4 Excluded (Did Not Receive Study Drug)

663 Included in Primary Efficacy Analysis 660 Included in Safety Analysis 3 Excluded (Did Not Receive Study Drug)

ties due to its facilitation of an adenosine triphosphatedependent potassium channel opening5 and anti-ischemic effects.6 In clinical studies, levosimendan increased cardiac output and lowered cardiac filling pressures and was associated with reducing cardiac symptoms, risk of death, and hospitalization.7-9 Unlike other positive inotropic agents, the primary actions of levosimendan are independent of interactions with -adrenergic receptors.10,11 Compared with the -adrenergic agonist dobutamine in the Levosimendan Infusion versus Dobutamine (LIDO) trial,12 levosimendan exerted superior hemodynamic effects and in secondary and post hoc analyses was associated with a lower risk of death after 31 and 180 days. Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) was the first survival trial performed in patients with ADHF, to our knowledge. The SURVIVE trial assessed the effect of short-term intravenous infusions of levosimendan or dobutamine on longterm survival. METHODS The SURVIVE trial was conducted at 75 centers in Austria, Finland, France, Ger1884

many, Israel, Latvia, Poland, Russia, and the United Kingdom. The study protocol was approved by independent ethics committees and was conducted in accordance with the Declaration of Helsinki13 and applicable regulatory requirements. This trial was designed, implemented, executed, and overseen by the study sponsor and steering committee. An independent data and safety monitoring board had access to unblinded data and periodically reviewed the safety results.
Study Patients

The study enrolled patients aged 18 years or older who provided written informed consent and were hospitalized with ADHF. All patients had an ejection fraction of 30% or less within the previous 12 months and required intravenous inotropic support, as evidenced by an insufficient response to intravenous diuretics and/or vasodilators, and at least 1 of the following at screening: (1) dyspnea at rest or mechanical ventilation for ADHF; (2) oliguria not as a result of hypovolemia; or (3) pulmonary capillary wedge pressure of 18 mm Hg or higher and/or cardiac index of 2.2 L/min per m2 or less.

SURVIVE was a randomized, doubleblind, multicenter, parallel-group study. Randomization was performed by a 2-step procedure (FIGURE 1). First, vials containing study drug were assigned a number using randomly permuted blocks. Second, patients were randomized centrally, using an interactive voice response system, to receive levosimendan or dobutamine at a ratio of 1:1. Randomization was stratified using a biased coin algorithm with previous ADHF and country as factors. During the treatment period, patients were randomized to receive 2 double-blind intravenous infusions: levosimendan and placebo for dobutamine in the levosimendan group or dobutamine and placebo for levosimendan in the dobutamine group. A loading dose of levosimendan (12 g/kg) or placebo for levosimendan was administered over 10 minutes, followed by an infusion (0.1 g/kg per minute) for 50 minutes; the rate was increased to 0.2 g/kg per minute for an additional 23 hours as tolerated. The infusion of dobutamine or placebo for dobutamine was initiated at a rate of 5 g/kg per minute and could be increased at the discretion of the investigator to a maximum rate of 40 g/kg per minute. The infusion was maintained as long as clinically appropriate (minimum of 24 hours) and was tapered according to each patients clinical status. Plasma B-type natriuretic peptide (BNP) levels were measured after 1, 3, and 5 days. Hospitalization or death was noted for the 180-day period. If pa-

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LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE

tients required additional inotropic support during the study period, the intention was to maintain the blind by readministering the patients original assigned study drug and dosing regimen. However, this was not mandated so failure to do so was not considered a protocol violation. If readministration occurred within 7 days of initial infusion, levosimendan was administered without a loading dose and at 0.1 g/kg per minute.
Study End Points

Table 1. Baseline Patient Demographics and Characteristics*

Levosimendan (n = 664) 493 (74) 627 (94) 67 (12) 79 (18) 116 (18) 70 (12) 84 (17) 586 (88) 453 (68) 412 (62) 405 (61) 324 (49) 317 (48) 310 (47) 205 (31) 503 (76) 572 (86) 24 (5) 1581 (1490) 1178 (573-2066) 336 (51) 463 (70) 336 (51) 523 (79) 241 (36) 50 (8) Dobutamine (n = 663) 463 (70) 625 (94) 66 (12) 79 (16) 116 (19) 70 (12) 83 (17) 585 (88) 455 (69) 419 (63) 429 (65) 308 (46) 308 (46) 318 (48) 223 (34) 502 (76) 562 (85) 24 (5) 1667 (1670) 1231 (583-2084) 333 (50) 451 (68) 366 (55) 523 (79) 252 (38) 34 (5)

Male sex White race Age, mean (SD), y Weight, mean (SD), kg Vital signs, mean (SD) Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, beats/min Cardiovascular history History of heart failure Myocardial infarction Mitral insufficiency Hypertension Atrial fibrillation/flutter Tricuspid insufficiency Stable angina pectoris Type 2 diabetes Initial hospitalization characteristics Ischemic etiology for acute heart failure NYHA class IV LVEF, mean (SD), % BNP level, pg/mL Mean (SD) Median (range) Cardiovascular medications prior to infusion -Blocking agents ACE inhibitor or ARB Aldosterone antagonists Intravenous diuretics Intravenous nitrates Intravenous dopamine

The primary end point of the study was all-cause mortality during the 180 days following randomization. Secondary end points included all-cause mortality during 31 days, change in BNP level from baseline to 24 hours, number of days alive and out of the hospital during the 180 days, change in patientassessed dyspnea at 24 hours, patientassessed global assessment at 24 hours, and cardiovascular mortality through 180 days. To monitor safety, adverse events were collected for 31 days following initial study drug administration and during all blinded drug readministrations.
Statistical Analyses

The sample size was based on the objective of assessing differences in allcause mortality between the levosimendan and dobutamine groups at 180 days. The trial was event-rate driven until 330 deaths had occurred, providing 85% power ( = .05) to detect a 25% relative risk reduction in mortality rates between the treatment groups, assuming the 180-day mortality rate was 25.3%. The originally targeted number of patients, based on LIDO,12 was 700 but was increased to 1320 following a blinded review of mortality after 131 deaths to achieve the target number of 330 deaths. To control the type I error due to 2 interim analyses, the Haybittle-Peto boundary was used and differences in risk between the 2 treatments at the end of the trial were considered significant at a P value of less than .05.

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; BNP, B-type natriuretic peptide; BP, blood pressure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association. *Values are expressed as number (percentage) unless otherwise indicated. Most recent within 12 months preceding randomization. The Axsym BNP assay (Abbott Laboratories, Abbott Park, Ill) was used. The normal level for BNP was less than 135 pg/mL in individuals who did not have heart failure. A dose of 2 g/kg per minute or less.

Figure 2. Effect of Dobutamine and Levosimendan Treatment on All-Cause Mortality During 180 Days Following the Start of Study Drug Infusion
1.0 0.8 0.6 0.4 0.2 0 0 No. at Risk Levosimendan Dobutamine 30 60 90 120 150 180 Cox Proportional Hazards P = .40

Probability of Survival

Levosimendan Dobutamine

Time Since Start of Study Drug Infusion, d

664 608 586 663 596 568 525 519 462 454

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LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE

Table 2. Primary, Secondary, and Post Hoc All-Cause Mortality End Points*
No. (%) of Patients Levosimendan Dobutamine (n = 664) (n = 663) Primary end point All-cause mortality at 180 d Secondary end point All-cause mortality at 31 d Mean change in BNP at 24 h from baseline, pg/mL Mean No. of days alive and out of the hospital during 180 d Dyspnea assessed at 24 h; mild improvement Global assessment at 24 h; mild improvement Cardiovascular mortality during 180 d Post hoc all-cause mortality 5d 14 d 90 d 173 (26) 79 (12) (n = 628) 631 120.2 544 (82) 531 (80) 157 (24) 29 (4) 59 (9) 139 (21) 185 (28) 91 (14) (n = 611) 397 116.6 550 (83) 537 (81) 171 (26) 40 (6) 69 (10) 138 (21) 0.90 (0.72-1.12) 0.72 (0.44-1.16) 0.84 (0.59-1.19) 0.99 (0.78-1.25) HR (95% CI) 0.91 (0.74-1.13) 0.85 (0.63-1.15) P Value .40 .29 .001 .30 .96 .99 .33 .17 .33 .91

lyzed using the Kruskal-Wallis test. Comparisons between treatment groups for the incidence rates of adverse events were performed using a Fisher exact test and mean change from baseline of other variables were performed by analysis of covariance with baseline as a covariate. Treatment differences in mean change from baseline in electrocardiogram and vital signs were tested by analysis of covariance with baseline as a covariate. Statistical analyses were performed using SAS version 8.2 (SAS Institute Inc, Cary, NC) and significance was reported at a P value of .05 or less. RESULTS
Patient Population

Abbreviations: BNP, B-type natriuretic peptide; CI, confidence interval; HR, hazard ratio. *Survival differences were tested for significance by the Cox proportional hazard regression model with treatment as the only covariate. Comparison of categorical variables such as dyspnea assessment, patients global assessment, and days alive and out of the hospital were performed by the Cochran-Mantel-Haenszel test with effect for treatment only. Changes in BNP levels were analyzed using the Kruskal-Wallis test. Unless otherwise indicated. Cox proportional hazards model was used for treatment effect only. Analysis of covariance model used with baseline value as covariate and treatment for main effect. Cochran-Mantel-Haenszel mean score test with effect for treatment only. Distribution from markedly improved to markedly worse.

Figure 3. Mean Change From Baseline in B-Type Natriuretic Peptide Levels at 1, 3, and 5 Days by Treatment Group
0

200 400 600

Dobutamine

Levosimendan 800 0 1 2 3 4 5

Time Since Start of Study Drug Infusion, d

There was a significantly greater mean (SE) change from baseline in plasma B-type natriuretic peptide levels in the levosimendan group compared with the dobutamine group at 1, 3, and 5 days after initiation of study drug infusion. P.001 at all 3 time points. Statistical significance was determined using KruskalWallis test with treatment effect.

Analysis of survival was based on a patients randomization in accordance with the intention-to-treat principle. Cumulative survival curves were constructed as time-to-event plots by Kaplan-Meier methods and differences were tested for signifi1886

cance by the Cox proportional hazard regression model, with treatment as the only covariate. The Cox model also was used to examine potential treatment subgroup interactions using treatment, subgroup, and treatment subgroup interaction as covariates. Prespecified subgroup analyses included the baseline variables of sex, age, previous ADHF, acute myocardial infarction at initial hospitalization, serum creatinine level, oliguria, -blocker use, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use, systolic blood pressure, heart rate, dyspnea at rest, and mechanical ventilation for ADHF. The Cox model within subgroups was further considered if the interaction P value was .10 or less. Comparison of categorical variables such as dyspnea assessment, patients global assessment, and number of days alive and out of the hospital was performed using the Cochran-MantelHaenszel test with effect for treatment only. Changes in BNP levels were ana-

A total of 1327 patients hospitalized with ADHF were randomized between March 2003 and December 2004 to either the levosimendan group (n = 664) or the dobutamine group (n = 663). Of this intention-to-treat population, 1320 patients (660 in each group) received study drug and were included in the safety population (Figure 1). Patients randomized to levosimendan or dobutamine were similar with respect to pretreatment characteristics (TABLE 1) and concomitant medications. Patients had increased BNP levels and the large majority (n = 1171; 88%) had previous ADHF. After the initial hour that includes loading dose, levosimendan was continuously infused at a mean (SD) rate of 0.2 (0.02) g/kg per minute for 23.4 (2.9) hours; dobutamine was infused at a rate of 5.9 (2.6) g/kg per minute for 39.3 (44.4) hours. During the 180day period, 102 (8%) patients (48 in the levosimendan group and 54 in the dobutamine group) received blinded readministration of study drug. Also, during the study period, 75 (11%) patients in levosimendan group received open-label dobutamine (n=72) or levosimendan (n=3) while 79 (12%) patients in the dobutamine group received open-label dobutamine (n=74) or levosimendan (n=5).

Mean Change From Baseline, pg/mL

JAMA, May 2, 2007Vol 297, No. 17 (Reprinted)

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LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE Primary and Secondary End Points

During the 180 days after study drug infusion, there were 173 deaths (26%) in the levosimendan group and 185 deaths in the dobutamine group (28%) (hazard ratio, 0.91 [95% confidence interval, 0.74-1.13] P = .40; FIGURE 2). Analysis of all-cause mortality at 31 days and cardiovascular mortality at 180 days also showed no difference between the treatment groups (TABLE 2). Plasma BNP levels decreased more in the levosimendan group than in the dobutamine group at 24 hours and at 3 and 5 days (all P.001) (FIGURE 3). Other secondary variables were similar between the treatment groups (Table 2). Subgroup analyses were performed to assess the influence of prespecified baseline characteristics on the difference in survival between patients in the levosimendan and dobutamine groups (TABLE 3 and TABLE 4). Most of the prespecified subgroup analyses showed no interactions. However, a prior history of heart failure at baseline did influence the between-group difference at 31 days (treatment prior heart failure interaction, P = .05) but not at 180 days. At 31 days, in the 88% of patients with a prior history of heart failure, there was a trend for lower risk of death in the levosimendan group compared with the dobutamine group. However, in the subgroup of patients without a prior history of heart failure (12%), there was a numerical increase in the levosimendan group.
Safety and Tolerability

pokalemia ( P = .02), and headache (P =.01) during the initial 31 days following study drug administration (TABLE 5). The treatment groups were similar with respect to frequency of hypotension, renal insufficiency, ventricular arrhythmias, or history of torsade de pointes. The QTc interval did not increase with levosimendan and did not differ between the 2 groups.

COMMENT Patients hospitalized for ADHF carry a high risk of death and rehospitalization in the months following admission.14,15 Available evidence suggests that the short-term risk may be influenced by treatment16 because several therapeutic agents including dobutamine, milrinone, and nesiritide have been associated with an early increase

Table 3. Influence of Prespecified Baseline Characteristics on the Difference in Survival at 31 Days*

Total No. of Patients Sex Female Male Age, y 65 65 History of CHF Yes No Prior use of -blocker Yes No Prior use of ACE inhibitor or ARB Yes No AMI as primary cause of hospitalization Yes No Serum creatinine level, mg/dL (mol/L) 2.5 (221) 2.5 (221) Oliguria Yes No Dyspnea at rest Yes No Mechanical ventilation for heart failure Yes No Heart rate, beats/min 83 83 Systolic blood pressure, mm Hg 100 100 371 956 501 826 1171 156 669 658 Mortality Rate, No./Total (%) Levosimendan 20/171 (12) 59/493 (12) 20/237 (8) 59/427 (14) 59/586 (10) 20/78 (26) 24/336 (7) 55/328 (17) Dobutamine 30/200 (15) 61/463 (13) 22/264 (8) 69/399 (17) 78/585 (13) 13/78 (17) 31/333 (9) 60/330 (18) HR (95% CI) 0.77 (0.43-1.35) 0.89 (0.62-1.28) 1.01 (0.55-1.84) 0.77 (0.55-1.10) 0.73 (0.52-1.03) 1.61 (0.80-3.25) 0.75 (0.44-1.28) 0.91 (0.63-1.32) P Value for Interaction .65

.47

.05

.55

914 413

41/463 (9) 38/201 (19)

38/451 (8) 53/212 (25)

1.05 (0.67-1.63) 0.72 (0.47-1.09)

.22

178 1149

23/83 (28) 56/581 (10)

30/95 (32) 61/568 (11)

0.83 (0.48-1.43) 0.89 (0.62-1.28)

.82

1237 87 101 1226 1184 133

63/620 (10) 16/44 (36) 13/49 (27) 66/615 (11) 67/595 (11) 11/64 (17)

75/617 (12) 16/43 (37) 19/52 (37) 72/611 (12) 76/589 (13) 13/69 (19)

0.82 (0.59-1.15) 0.97 (0.48-1.95) 0.67 (0.33-1.38) 0.90 (0.64-1.26) 0.86 (0.62-1.20) 0.88 (0.39-1.97)

.68

.44

Systolic and diastolic blood pressure initially declined more in the levosimendan group than in the dobutamine group. Following cessation of the study drug infusions, these differences subsided (FIGURE 4). Heart rate increased more in the levosimendan group than in the dobutamine group (Figure 4) and remained elevated through 5 days. Compared with dobutamine-treated patients, levosimendan-treated patients were less likely to experience cardiac failure (P =.02) and more likely to experience atrial fibrillation (P =.05), hy-

.96

24 1302 705 622

3/12 (25) 75/651 (12) 25/339 (7) 54/325 (17)

5/12 (42) 86/651 (13) 35/366 (10) 56/297 (19)

0.52 (0.12-2.20) 0.86 (0.63-1.17) 0.75 (0.45-1.26) 0.87 (0.59-1.26)

.49

.66

271 1051

23/135 (17) 55/527 (10)

32/136 (24) 58/524 (11)

0.69 (0.40-1.19) 0.93 (0.64-1.35)

.37

Abbreviations: ACE, angiotensin-converting enzyme; AMI, acute myocardial infarction; ARB, angiotensin II receptor blocker; CHF, congestive heart failure; CI, confidence interval; HR, hazard ratio. *The Cox model was used to examine potential treatment subgroup interactions using treatment subgroup interaction as covariates.

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LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE

Table 4. Influence of Prespecified Baseline Characteristics on Survival at 180 Days*

Total No. of Patients Sex Female Male Age, y 65 65 History of CHF Yes No Prior use of -blocker Yes No Prior use of ACE inhibitor or ARB Yes No AMI as primary cause of hospitalization Yes No Serum creatinine level, mg/dL (mol/L) 2.5 (221) 2.5 (221) Oliguria Yes No Dyspnea at rest Yes No Mechanical ventilation for heart failure Yes No Heart rate, beats/min 83 83 Systolic blood pressure, mm Hg 100 100 371 956 501 826 1171 156 669 658 Mortality Rate, No./Total (%) Levosimendan 45/171 (26) 128/493 (26) 54/237 (23) 119/427 (28) 148/586 (25) 25/78 (32) 65/336 (19) 108/328 (33) Dobutamine 58/200 (29) 127/463 (27) 56/264 (21) 129/399 (32) 165/585 (28) 20/78 (26) 72/333 (22) 113/330 (34) HR (95%CI) 0.89 (0.60-1.32) 0.93 (0.73-1.19) 1.08 (0.74-1.57) 0.83 (0.65-1.06) 0.87 (0.70-1.09) 1.31 (0.73-2.37) 0.87 (0.62-1.22) 0.95 (0.73-1.24) P Value for Interaction .86

.25

.19

.69

914 413

104/463 (23) 69/201 (34)

98/451 (22) 87/212 (41)

1.04 (0.79-1.38) 0.77 (0.56-1.06)

.15

178 1149

27/83 (33) 146/581 (25)

40/95 (42) 145/568 (26)

0.72 (0.44-1.17) 0.98 (0.78-1.23)

.23

1237 87 101 1226 1184 133

149/620 (24) 24/44 (55) 20/49 (41) 153/615 (25) 151/595 (25) 21/64 (33)

164/617 (27) 21/43 (49) 27/52 (52) 158/611 (26) 161/589 (27) 22/69 (32)

0.88 (0.71-1.10) 1.10 (0.61-1.99) 0.69 (0.39-1.24) 0.95 (0.76-1.19) 0.92 (0.73-1.14) 0.99 (0.54-1.80)

.48

.26

.80

24 1302 705 622

6/12 (50) 166/651 (26) 78/339 (23) 95/325 (29)

5/12 (42) 180/651 (28) 88/366 (24) 97/297 (33)

1.05 (0.32-3.49) 0.90 (0.73-1.12) 0.93 (0.69-1.26) 0.88 (0.66-1.17)

.75

.80

271 1051

53/135 (39) 129/527 (23)

62/136 (46) 121/524 (23)

0.80 (0.55-1.15) 0.97 (0.76-1.25)

.39

Abbreviations: ACE, angiotensin-converting enzyme; AMI, acute myocardial infarction; ARB, angiotensin II receptor blocker; CHF, congestive heart failure; CI, confidence interval; HR, hazard ratio. *The Cox model was used to examine potential treatment subgroup interactions using treatment subgroup interaction as covariates.

in the risk of death.1,17,18 In this study, we compared levosimendan, which sensitizes the cardiac myofilament response to calcium and facilitates the opening of adenosine triphosphate dependent potassium channels with minimal effect on intracellular cyclic adenosine monophosphate, to dobutamine, the most widely used therapy for ADHF, which predominately acts by increasing intracellular cyclic adenosine monophosphate. In the LIDO trial,12 those assigned to levosimendan had a lower risk of death than those assigned to dobutamine but this benefit was not the primary end point of the study. The SURVIVE study is the first prospective, randomized trial to monitor long-term survival in patients with ADHF. The results revealed no significant difference between levosimendan and dobutamine in all-cause mortality at 31 and 180 days after study drug infusion. The SURVIVE study demonstrated that levosimendan-treated patients had marked decreases in BNP level compared with dobutamine-treated patients through 5 days. The contrast in the effects of levosimendan over dobutamine is congruent with the pharmacokinetics of both drugs; the active metabolite of levosimendan peaks approximately 3 days after the start of the infusion and has a half-life of 80 hours.19 In contrast, dobutamine has a shorter half-life and no known active metabolite. Therefore, it is noteworthy that in the SURVIVE trial numerical differences in survival between the

Figure 4. Mean Change From Baseline in Systolic Blood Pressure, Diastolic Blood Pressure, and Heart Rate Through 5 Days by Treatment Group
Systolic Blood Pressure 1 0 0 1 2 3 4 5 6 0 6 24 48 72 96 120 Levosimendan 1 2 3 Levosimendan 4 5 6 0 6 24 48 72 96 120 Diastolic Blood Pressure 8 Dobutamine 6 4 2 0 2 4 6 0 6 24 48 72 96 120 Dobutamine Heart Rate Levosimendan

Mean Change From Baseline, mm Hg

Mean Change From Baseline, mm Hg

Dobutamine

Study Assessment, h

Study Assessment, h

Mean Change From Baseline, Beats/min

Study Assessment, h

Error bars indicate SEs. 1888 JAMA, May 2, 2007Vol 297, No. 17 (Reprinted)

2007 American Medical Association. All rights reserved.

LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE

2 drugs were seen early in the trial immediately following the cessation of treatment (ie, hazard ratio, 0.72 [95% confidence interval, 0.44-1.16] at 5 days post hoc analysis) but these hazard ratio differences dissipated in the absence of continued therapy during longterm follow-up. A second explanation for the lack of mortality difference between the treatment groups during long-term therapy is that levosimendan and dobutamine may differ in their survival effects only in a subgroup of ADHF patients. In SURVIVE, randomization was stratified by previous heart failure based on earlier evidence that it might influence ADHF mortality20 and treatment differences. Therefore, it is noteworthy that a history of heart failure influenced the treatment differences we observed. Specifically, treatment differences in favor of levosimendan at 31 days were more apparent in patients with a prior history of heart failure than in those with recent-onset heart failure, possibly because of the greater use of -blockers in patients with chronic heart failure. -Receptor antagonists may interfere with the hemodynamic benefits of dobutamine21,22 or potentiate the circulatory actions of levosimendan12,23 or both. A third explanation may be that a different dobutamine dosing strategy in the SURVIVE study prohibited the replication of the 180-day mortality in the LIDO study,12 a hemodynamic study in which all patients had a pulmonary artery catheter inserted. In SURVIVE, the tailored approach was different from the dobutamine dosing regimen used in the LIDO study in which patients in the dobutamine group initially received 5 g/kg per minute and were up-titrated to 10 g/kg per minute if hemodynamic goals were not achieved. In the SURVIVE trial, the dobutamine dose could have been increased up to 40 g/kg per minute to achieve clinical goals, however it was administered at a relatively low dose of 6 g/kg per minute and for an average of 39 hours. The dobutamine dosing regimen was determined by the treating physician in a blinded fashion and accord-

ing to the patients needs. Additionally, the dobutamine infusion was discontinued after 24 hours in the LIDO study. The individualized dosing strategy adopted for dobutamine in the SURVIVE
Table 5. Treatment-Emergent Adverse Events*

trial may have produced the 180-day mortality of 28% compared with 38% in the LIDO study. By contrast, levosimendan was given in a fixed manner in both the SURVIVE and LIDO studies with the

No. (%) of Patients Levosimedan (n = 660) 518 (78.5) 195 (29.5) 102 (15.5) 81 (12.3) 62 (9.4) 60 (9.1) 55 (8.3) 52 (7.9) 45 (6.8) 40 (6.1) 37 (5.6) 33 (5.0) 32 (4.8) 30 (4.5) 30 (4.5) 26 (3.9) 26 (3.9) 24 (3.6) 22 (3.3) 22 (3.3) 21 (3.2) 20 (3.0) 20 (3.0) 20 (3.0) 19 (2.9) 19 (2.9) 18 (2.7) 16 (2.4) 15 (2.3) 15 (2.3) 15 (2.3) 15 (2.3) 14 (2.1) 13 (2.0) 12 (1.8) 12 (1.8) 9 (1.4) 8 (1.2) 9 (1.4) 7 (1.1) 7 (1.1) Dobutamine (n = 660) 502 (76.1) 217 (32.9) 92 (13.9) 112 (17.0) 39 (5.9) 40 (6.1) 31 (4.7) 48 (7.3) 49 (7.4) 24 (3.6) 29 (4.4) 33 (5.0) 47 (7.1) 21 (3.2) 24 (3.6) 22 (3.3) 28 (4.2) 22 (3.3) 24 (3.6) 19 (2.9) 30 (4.5) 26 (3.9) 19 (2.9) 18 (2.7) 16 (2.4) 21 (3.2) 10 (1.5) 7 (1.1) 23 (3.5) 19 (2.9) 17 (2.6) 16 (2.4) 7 (1.1) 18 (2.7) 13 (2.0) 18 (2.7) 17 (2.6) 17 (2.6) 15 (2.3) 14 (2.1) 0 P Value .32 .21 .48 .02 .02 .05 .01 .76 .75 .05 .38 .99 .10 .25 .49 .66 .89 .88 .88 .75 .25 .45 .99 .87 .73 .87 .18 .09 .25 .60 .86 .99 .19 .47 .99 .36 .16 .10 .30 .19 .02

Any adverse event Any serious adverse event Hypotension Cardiac failure Hypokalemia Atrial fibrillation Headache Ventricular tachycardia Nausea Ventricular extrasystoles Insomnia Tachycardia Chest pain Diarrhea Pneumonia Congestive cardiac failure Constipation Renal failure Vomiting Pyrexia Urinary tract infection Cardiac arrest Anxiety Pulmonary edema Dizziness Cough Pain in extremity Pruritus Cardiogenic shock Ventricular fibrillation Anemia Hyperkalemia Epistaxis Back pain Muscle spasms Angina pectoris Dyspnea Bradycardia Hypertension Cataract Agitation

*Safety population includes any patient who received study drug. Calculated using the Fisher exact test. A serious adverse event was defined as any event in a study patient that was fatal, life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or relevant disability or incapacity, was a congenital anomaly/ birth defect, or any other medically significant event (eg, an intervention to prevent one of the listed outcomes). Term based on investigator reporting and may or may not represent similar type of event as congestive cardiac failure (below).

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LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE

same 180-day all-cause mortality rate of 26%. Accordingly, future trials should consider allowing the dose of levosimendan to also be individualized. Compared with dobutamine-treated patients, levosimendan-treated patients were more likely to experience an initial decrease in systolic and diastolic blood pressure (Figure 4). The latter, likely related to the mode of administration of levosimendan and especially to the bolus dose, might be responsible for the occurrence of atrial fibrillation and possibly to other detrimental effects such as death. Accordingly, future trials should investigate the optimal mode of administration of levosimendan. Hypokalemia was consistently observed in SURVIVE as in other trials.7,12 Mechanism of hypokalemia remains to be elucidated. In conclusion, the SURVIVE trial demonstrated no survival difference between levosimendan and dobutamine during long-term follow-up despite evidence for an early reduction of plasma BNP level for levosimendan. These findings may be related to the short duration of treatment in the trial, a selective effect of levosimendan in specific subgroups, or the lack of a true difference between the 2 drugs. Further studies are needed to distinguish between these possibilities.
Author Contributions: Drs Mebazaa and Nieminen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Mebazaa, Nieminen, Packer, Cohen-Solal, Kleber, Pocock, Po der, Kivikko. Acquisition of data: Nieminen, Padley, Po der, Kivikko. Analysis and interpretation of data: Mebazaa, Nieminen, Packer, Cohen-Solal, Kleber, Pocock, Thakkar, Padley, Po der. Drafting of the manuscript: Mebazaa, Nieminen, Packer, Cohen-Solal, Kleber, Pocock, Thakkar, Padley. Critical revision of the manuscript for important intellectual content: Mebazaa, Nieminen, Packer, Cohen-Solal, Kleber, Pocock, Thakkar, Padley, Po der, Kivikko. Statistical analysis: Pocock, Padley. Obtained funding: Padley, Po der. Administrative, technical, or material support: Thakkar, Padley, Po der, Kivikko. Study supervision: Mebazaa, Nieminen, Packer, Cohen-Solal, Kleber, Thakkar, Padley. Financial Disclosures: Dr Mebazaa reported being a consultant for Abbott, Orion Pharma, Protein Design Biopharma, and Sigma-Tau and receiving honoraria from Abbott, Guidant, and Edwards Life Sciences. Dr Nieminen reported being a consultant for Abbott, Orion Pharma, Scios, Medtronic, and Pfizer. Dr CohenSolal reported being a consultant for and receiving 1890

honoraria from Abbott, Orion Pharma, Protein Design Biopharma, AstraZeneca, Amgen, Takeda, and Menarini. Dr Kleber reported receiving research grants from Orion Pharma and being a consultant for Abbott and Orion Pharma. Dr Pocock reported being a consultant for Abbott, Orion Pharma, and Scios. Dr Packer reported being a consultant for Abbott and Orion Pharma. Drs Thakkar and Padley are Abbott employees. Drs Po der and Kivikko are Orion Pharma employees. Funding/Support: Abbott and Orion Pharma funded the SURVIVE trial and data analysis activities. Role of the Sponsor: Analyses of study results were performed, with supervision from the sponsor, by ICON Clinical Research (Dublin, Ireland, and North Wales, Pa). The sponsor was involved in the management, analysis, and interpretation of the data. Abbott and Orion Pharma reviewed the manuscript prior to submission. Independent Statistical Review: Raphae l Porcher, PhD (Department of Biostatistics, Universite Paris Diderot and University Hospital Saint-Louis, Paris, France), received full access to the study protocol, amendments, statistical analysis plan, and raw database. In his opinion, the statistical analysis plan is appropriate to the study as is the way that the results are presented in the manuscript. From the raw database, Dr Porcher recomputed the time to death during the 180 days following the start of the study drug (primary end point) of all 1327 patients randomized in the study and checked the ones used by Abbott (Abbott Park, Ill) for analysis. Dr Porcher then performed the main analysis on an intent-to-treat basis as well as by subgroup analyses for the presence of previous chronic heart failure, which were prespecified in the statistical analysis plan. The results of these analyses are in complete agreement with that reported in this article. Dr Porcher additionally performed several sensitivity analyses specified in the statistical analysis plan or potentially relevant, which confirmed the results. Compensation for Dr Porchers work was paid to the Universite Paris Diderot by Abbott. Steering Committee: Alexandre Mebazaa (chair), Department of Anesthesiology and Critical Care Medicine, Universite Paris Diderot and Hospital Lariboisire, Paris, France; Markku S. Nieminen, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland; Milton Packer, Department of Clinical Sciences, University of Texas Southwestern Medical School, Dallas; Alain Cohen-Solal, Department of Cardiology, Universite Paris Diderot and Hospital Lariboisire, Paris, France; Franz X. Kleber, Department of Internal Medicine, Charite Medical School, Berlin, Germany; Stuart J. Pocock, Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, England. Data and Safety Monitoring Board: John Cleland (chair), Castle Hill Hospital, Cottingham, England; Dan Langrois, CHU Brabois, Vandoeuvre-les-Nancy, France; Viatcheslav Mareev, Cardiology Research Center, Moscow, Russia; Richard Kay, PAREXEL International, South Yorkshire, England. SURVIVE Trial Investigators: Austria: Alexander Geppert (Wilhelminenspital der Stadt Wien, Wien); Thomas Martys (Kaiserin-Elisabeth-Spital der Stadt Wien, Wien); Johannes Mlczoch (Krankenhaus der Stadt Wien Lainz, Wien); Jo rg Slany (Krankenanstalt Rudolfstiftung, Wien). Finland: Juhani Airaksinen (Turku University Central Hospital, Turku); Veli-Pekka Harjola (Helsinki University Central Hospital); Heikki Huikuri (University of Oulu, Oulu); Pirjo Ma ntyla (Central Hospital of North Karelia, Joensuu); John Melin (Central Hospital of Central Finland, Jyva skyla ); Keijo Peuhkurinen (Kuopio University Hospital, Kuopio). France: Philippe Asseman (CHU Lille, Lille); Jean-Franc ois Aupetit (CH Saint-Joseph et Saint-Luc, Lyon); Michel Barboteu (Centre Me dical dEvecquemont, Meulan); Marc Benacerraf (Centre Cardiologique du Nord, Saint De-

nis); Jean-Marc Boulenc (Clinique Saint Joseph, Colmar); Alain Cariou (Ho pital Cochin Port Royal, Paris); Alain Cohen-Solal (Ho pital Beaujon, Clichy); Pierre Coste (Ho pital Cardiologique Haut Leveque, Pessac); Jean Luc Dubois-Rande (Ho pital Henri Mondor, Creteil); Olivier Dubourg (Ho pital Ambroise Pare , Boulogne Billancourt); Marc Feissel (Centre Hospitalier Belfort/Montbeliard, Belfort); Franc ois Funck (Centre Hospitalier Rene Dubos, Pontoise); Michel Galinier (Ho pital Rangueil, Toulouse); Pierre Gibelin (Ho pital Pasteur, Nice); Yannick Gottwalles (Clinique Saint Joseph, Colmar); Louis Guize (Ho pital Europe en Georges Pompidou, Paris); Gilbert Habib (CHU de la Timone, Marseille); Ivan Laurent (Institut Hospitalier Jacques Cartier, Massy); Herve Le Marec (Ho pital Nord Laennec, Nantes-Saint-Herblain); Bruno Levy (Ho pital Central Nancy, Nancy); Alexandre Mebazaa (Ho pital Lariboisire, Paris); Gilles Montalescot (Ho pital Pitie Salpe trire, Paris); Ge rald Roul (Ho pital de Hautepierre, Strasbourg); Re mi Sabatier (CHU Co te de Nacre, Caen); Pierre Squara (Clinique Ambroise Pare , Neuilly sur Seine); Gabriel Steg (Ho pital Bichat-Claude Bernard, Paris); Jean-Louis Teboul (CHU Bice tre, Le Kremlin-Bicetre); Paul Touboul (Ho pital Cardiologique Louis Pradel, Bron); Philippe Vignon (Ho pital Dupuytren, Limoges); Simon Weber (Ho pital Cochin Port Royal, Paris); Faies Zannad (CHU de Nancy, Vandoeuvre les Nancy); Robin Zelinsky (Clinique Saint-Sauveur, Mulhouse). Germany: Gerhard Bauriedel (Universita tsklinikum Bonn, Bonn); Michael Bo hm (Universita tskliniken des Saarlandes, Homburg/Saar); Michael Buerke (Klinikum der Medizinischen Fakulta t der Martin-Luther-Universita t Halle-Wittenberg, Halle [Saale]); Angelika Costard-Ja ckle (AK St Georg, Hamburg); Aly El-Banayosy (Herz-u Diabeteszentrum NordrheinWestfalen, Universita tsklinik der Ruhr-Universita t Bochum, Bad Oeynhausen); Gerd Hasenfub (Universita tsklinikum Go ttingen, Go ttingen); Franz Xaver Kleber (Unfallkrankenhaus Berlin, Berlin); Veselin Mitrovic (Kerckhoff Klinik GmbH, Bad Nauheim); Thomas Mu nzel (Universita tsklinikum Hamburg-Eppendorf, Hamburg); Klaus Pethig (Klinik fu r Innere Medizin III der Friedrich Schiller Universita t Jena, Jena); Andrew Remppis (Medizinische Universita tsklinik und Poliklinik, Heidelberg); Peter Schuster (St Marien Krankenhaus Siegen, Siegen); Robert Schwinger (Universita t zu Ko ln, Ko ln [Lindenthal]); Ruth Strasser (Medizinische Klinik II/Kardiologie, Dresden). Israel: Jonathan Balkin (Shaare Zedek Medical Center, Jerusalem); Tuvia Ben Gal (Rabin Medical Center, Beilinson Campus, Petah Tikva); Daniel David (Meir Hospital, Sapir Medical Center, Kfar Saba); Dov Freimark (Sheba Medical Center, Tel Hashomer); Andre Keren (Bikur Holim Hospital, Jerusalem); Tiberiu Rosenfeld (Haemek Medical Center, Afula); Yoseph Rozenman (Wolfson Medical Center, Holon). Latvia: Galina Dormidontova (Daugavpils Central Regional Hospital, Daugavpils); Maija Keisa (Valmiera Hospital, Valmiera); Janis Lacis (P. Stradina Clinical University Hospital, Riga); Alfreds Libins (Liepaja Hospital, Liepaja); Dace Meldere (Riga Clinical Hospital Gailezers, Riga); Jurijs Verbovenko (Riga First Hospital, Riga). Poland: Jerzy Adamus (Central Military Hospital, Warszawa); Marek Dabrowski (Szpital Bielanski, Warszawa); Robert Gil (Department of Invasive Cardiology, Warszawa); Jerzy Korewicki (Institute of Cardiology, Warszawa); Maria Krzeminska-Pakula (Bieganski Hospital, Lodz); Grzegorz Opolski (Medical University ul Banacha 1a, Warszawa); Wieslawa Piwowarska ( Jagiellonian University School of Medicine, Cracow); Lech Polonski (Silesian Centre of Heart Diseases, Zabrze). Russia: Igor N. Bokarev (Moscow Medical Academy, Moscow); Nikolai A. Gratsiansky (Hospital No. 29, Moscow); Victor A. Lyusov (Russian Medical University, Moscow); Valentin S. Moiseyev (Russian Peoples Friendship University, Moscow); Mikhail Y. Ruda (Russian Cardiology Research Centre, Moscow); Raisa I. Stryuk, Sergey N. Tereschenko, and Vladimir S. Zadionchenko (Moscow

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LEVOSIMENDAN VS DOBUTAMINE IN ACUTE HEART FAILURE

State Medico-Stomatological University, Moscow); Dmitry A. Zateyshchikov (Central Clinical Hospital of Russian Government Medical Centre, Moscow). United Kingdom: Sanjay Arya (Royal Albert Edward Infirmary, Wigan); Craig Barr (Russells Hall Hospital, West Midlands); John Berridge (Leeds General Infirmary, Leeds); Henry Dargie (Clinical Research Institute, Glasgow); Gregory Lip (University Department of Medicine, Birmingham); Bernard Prendergast (Wythenshawe Hospital, Manchester); Andrew Rhodes (St Georges Hospital, London); Roxy Senior (Northwick Park Hospital, Harrow); Mervyn Singer (Middlesex Hospital, London). Acknowledgment: We are grateful to Thea Nieminen, RN, Toni Sarapohja, MSc (Orion Pharma, Espoo, Finland), and Nancy Chou, MS, RD, Leticia DelgadoHerrera RPh, MS, Stefan Hergenroeder, PhD, Bidan Huang, PhD, Brigitte Kalsch, MD, Udo Legler, MD, Michael Marshall, PharmD, and Greg Schulz (Abbott, Abbott Park, Ill) for their role in coordinating the efforts of ICON Clinical Research, the 2 sponsors, and the steering committee. All persons acknowledged did not receive compensation for their involvement with this work. 5. Yokoshiki H, Katsube Y, Sunagawa M, Sperelakis N. Levosimendan, a novel Ca2 sensitizer, activates the glibenclamide-sensitive K channel in rat arterial myocytes. Eur J Pharmacol. 1997;333:249-259. 6. Kersten JR, Montgomery MW, Pagel PS, Warltier DC. Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels. Anesth Analg. 2000;90:5-11. 7. Nieminen MS, Akkila J, Hasenfuss G, et al. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol. 2000;36:19031912. 8. Slawsky MT, Colucci WS, Gottlieb SS, et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation. 2000; 102:2222-2227. 9. Moiseyev VS, Poder P, Andrejevs N, et al. Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction: a randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J. 2002;23:1422-1432. 10. Haikala H, Kaheinen P, Levijoki J, Linden IB. The role of cAMP- and cGMP-dependent protein kinases in the cardiac actions of the new calcium sensitizer, levosimendan. Cardiovasc Res. 1997;34:536-546. 11. Kaheinen P, Pollesello P, Hertelendi Z, et al. Positive inotropic effect of levosimendan is correlated to its stereoselective Ca2-sensitizing effect but not to stereoselective phosphodiesterase inhibition. Basic Clin Pharmacol Toxicol. 2006;98:74-78. 12. Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet. 2002;360:196-202. 13. World Medical Association. Declaration of Helsinki: recommendations guiding physicians in biomedical research involving human subjects. Amended at: the 52nd World Medical Association General Assembly; October 2000; Edinburgh, Scotland. http: //www.wma.net/e/policy/pdf/17c.pdf. Accessibility verified March 29, 2007. 14. Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;287: 1531-1540. 15. OConnor CM, Stough WG, Gallup DS, Hasselblad V, Gheorghiade M. Demographics, clinical characteristics, and outcomes of patients hospitalized for decompensated heart failure: observations from the IMPACT-HF registry. J Card Fail. 2005;11:200-205. 16. Zannad F, Mebazaa A, Juilliere Y, et al. Clinical profile, contemporary management and one-year mortality in patients with severe acute heart failure syndromes: the EFICA study. Eur J Heart Fail. 2006;8:697705. 17. Thackray S, Easthaugh J, Freemantle N, Cleland JG. The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure: a metaregression analysis. Eur J Heart Fail. 2002;4:515-529. 18. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA. 2005; 293:1900-1905. 19. Kivikko M, Antila S, Eha J, Lehtonen L, Pentikainen PJ. Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure. Int J Clin Pharmacol Ther. 2002;40:465-471. 20. Nieminen MS, Brutsaert D, Dickstein K, et al. EuroHeart failure survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J. 2006;27:2725-2736. 21. Metra M, Nodari S, DAloia A, et al. Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure: a randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol. J Am Coll Cardiol. 2002;40:12481258. 22. Lowes BD, Tsvetkova T, Eichhorn EJ, Gilbert EM, Bristow MR. Milrinone versus dobutamine in heart failure subjects treated chronically with carvedilol. Int J Cardiol. 2001;81:141-149. 23. Bo di A, Szilagyi S, Edes I, Papp Z. The cardiotonic effects of levosimendan in guinea pig hearts are modulated by beta-adrenergic stimulation. Gen Physiol Biophys. 2003;22:313-327.

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(Reprinted) JAMA, May 2, 2007Vol 297, No. 17 1891