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Figure 1. Participant Flow Through the Study
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Figure 2. Effect of Dobutamine and Levosimendan Treatment on All-Cause Mortality During 180 Days Following the Start of Study Drug Infusion
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Figure 3. Mean Change From Baseline in B-Type Natriuretic Peptide Levels at 1, 3, and 5 Days by Treatment Group
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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 Kruskal-Wallis test with treatment effect.

Figure 4. Mean Change From Baseline in Systolic Blood Pressure, Diastolic Blood Pressure, and Heart Rate Through 5 Days by Treatment Group
Image description not available.

Error bars indicate SEs.

Table 1. Baseline Patient Demographics and Characteristics*
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Table 2. Primary, Secondary, and Post Hoc All-Cause Mortality End Points*
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Table 3. Influence of Prespecified Baseline Characteristics on the Difference in Survival at 31 Days*
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Table 4. Influence of Prespecified Baseline Characteristics on Survival at 180 Days*
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Table 5. Treatment-Emergent Adverse Events*
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1.
Cuffe MS, Califf RM, Adams KF Jr.  et al.  Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial.  JAMA. 2002;287:1541-1547PubMedArticle
2.
Bayram M, De Luca L, Massie MB, Gheorghiade M. Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes.  Am J Cardiol. 2005;96:(6A)  47G-58GPubMedArticle
3.
Haikala H, Kaivola J, Nissinen E, Wall P, Levijoki J, Linden IB. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan.  J Mol Cell Cardiol. 1995;27:1859-1866PubMedArticle
4.
Pollesello P, Ovaska M, Kaivola J.  et al.  Binding of a new Ca2+ sensitizer, levosimendan, to recombinant human cardiac troponin C: a molecular modelling, fluorescence probe, and proton nuclear magnetic resonance study.  J Biol Chem. 1994;269:28584-28590PubMed
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;333:249-259PubMedArticle
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;90:5-11PubMedArticle
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;36:1903-1912PubMedArticle
8.
Slawsky MT, Colucci WS, Gottlieb SS.  et al.  Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure.  Circulation. 2000;102:2222-2227PubMedArticle
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;23:1422-1432PubMedArticle
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;34:536-546PubMedArticle
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;98:74-78PubMedArticle
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;360:196-202PubMedArticle
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;287:1531-1540PubMedArticle
15.
O'Connor 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;11:200-205PubMedArticle
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;8:697-705PubMedArticle
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 meta-regression analysis.  Eur J Heart Fail. 2002;4:515-529PubMedArticle
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;293:1900-1905PubMedArticle
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;40:465-471PubMed
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;27:2725-2736PubMedArticle
21.
Metra M, Nodari S, D'Aloia 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;40:1248-1258PubMedArticle
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;81:141-149PubMedArticle
23.
Bódi 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;22:313-327PubMed
Original Contribution
May 2, 2007

Levosimendan vs Dobutamine for Patients With Acute Decompensated Heart FailureThe SURVIVE Randomized Trial

Author Affiliations
 

Author Affiliations: Departments of Anesthesiology (Dr Mebazaa), Critical Care Medicine (Dr Mebazaa), and Cardiology (Dr Cohen-Solal), Université Paris Diderot and Hospital Lariboisière 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, Charité Medical School, Berlin, Germany (Dr Kleber); Medical Statistics Unit, London School of Hygiene 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 Põder and Kivikko).

JAMA. 2007;297(17):1883-1891. doi:10.1001/jama.297.17.1883
Context

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, double-blind 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

Acute decompensated heart 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 properties due to its facilitation of an adenosine triphosphate–dependent 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.79 Unlike other positive inotropic agents, the primary actions of levosimendan are independent of interactions with β-adrenergic receptors.10,11 Compared with the β-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 long-term survival.

METHODS

The SURVIVE trial was conducted at 75 centers in Austria, Finland, France, Germany, 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.

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 μg/kg per minute or digitalis); history of torsade de pointes; and serum creatinine level higher than 5.1 mg/dL (450 μmol/L) or dialysis.

Study Plan

SURVIVE was a randomized, double-blind, 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 μg/kg) or placebo for levosimendan was administered over 10 minutes, followed by an infusion (0.1 μg/kg per minute) for 50 minutes; the rate was increased to 0.2 μg/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 μg/kg per minute and could be increased at the discretion of the investigator to a maximum rate of 40 μg/kg per minute. The infusion was maintained as long as clinically appropriate (minimum of 24 hours) and was tapered according to each patient's 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 patients required additional inotropic support during the study period, the intention was to maintain the blind by readministering the patient's 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 μg/kg per minute.

Study End Points

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 patient-assessed dyspnea at 24 hours, patient-assessed 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 all-cause mortality between the levosimendan and dobutamine groups at 180 days. The trial was event-rate driven until 330 deaths had occurred, providing 85% power (α = .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.

Analysis of survival was based on a patient's 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 significance 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, β-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-Mantel-Haenszel test with effect for treatment only. Changes in BNP levels were analyzed 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

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) μg/kg per minute for 23.4 (2.9) hours; dobutamine was infused at a rate of 5.9 (2.6) μg/kg per minute for 39.3 (44.4) hours. During the 180-day 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).

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

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), hypokalemia (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 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 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 long-term 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 β-blockers in patients with chronic heart failure. β-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 μg/kg per minute and were up-titrated to 10 μg/kg per minute if hemodynamic goals were not achieved. In the SURVIVE trial, the dobutamine dose could have been increased up to 40 μg/kg per minute to achieve clinical goals, however it was administered at a relatively low dose of 6 μg/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 according to the patient's needs. Additionally, the dobutamine infusion was discontinued after 24 hours in the LIDO study. The individualized dosing strategy adopted for dobutamine in the SURVIVE 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 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.

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Article Information

Corresponding Author: Alexandre Mebazaa, MD, PhD, Hospital Lariboisière, 2 Rue A Paré, Paris, France 75475 Cedex 10 (alexandre.mebazaa@lrb.aphp.fr).

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, Põder, Kivikko.

Acquisition of data: Nieminen, Padley, Põder, Kivikko.

Analysis and interpretation of data: Mebazaa, Nieminen, Packer, Cohen-Solal, Kleber, Pocock, Thakkar, Padley, Põder.

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, Põder, Kivikko.

Statistical analysis: Pocock, Padley.

Obtained funding: Padley, Põder.

Administrative, technical, or material support: Thakkar, Padley, Põder, 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 Cohen-Solal reported being a consultant for and receiving 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 Põder 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: Raphaël Porcher, PhD (Department of Biostatistics, Université 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 Porcher's work was paid to the Université Paris Diderot by Abbott.

Steering Committee: Alexandre Mebazaa (chair), Department of Anesthesiology and Critical Care Medicine, Université Paris Diderot and Hospital Lariboisière, 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, Université Paris Diderot and Hospital Lariboisière, Paris, France; Franz X. Kleber, Department of Internal Medicine, Charité 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); Jörg 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 Mäntylä (Central Hospital of North Karelia, Joensuu); John Melin (Central Hospital of Central Finland, Jyväskylä); Keijo Peuhkurinen (Kuopio University Hospital, Kuopio). France: Philippe Asseman (CHU Lille, Lille); Jean-François Aupetit (CH Saint-Joseph et Saint-Luc, Lyon); Michel Barboteu (Centre Médical d’Evecquemont, Meulan); Marc Benacerraf (Centre Cardiologique du Nord, Saint Denis); Jean-Marc Boulenc (Clinique Saint Joseph, Colmar); Alain Cariou (Hôpital Cochin Port Royal, Paris); Alain Cohen-Solal (Hôpital Beaujon, Clichy); Pierre Coste (Hôpital Cardiologique Haut Leveque, Pessac); Jean Luc Dubois-Rande (Hôpital Henri Mondor, Creteil); Olivier Dubourg (Hôpital Ambroise Paré, Boulogne Billancourt); Marc Feissel (Centre Hospitalier Belfort/Montbeliard, Belfort); François Funck (Centre Hospitalier René Dubos, Pontoise); Michel Galinier (Hôpital Rangueil, Toulouse); Pierre Gibelin (Hôpital Pasteur, Nice); Yannick Gottwalles (Clinique Saint Joseph, Colmar); Louis Guize (Hôpital Européen Georges Pompidou, Paris); Gilbert Habib (CHU de la Timone, Marseille); Ivan Laurent (Institut Hospitalier Jacques Cartier, Massy); Hervé Le Marec (Hôpital Nord Laennec, Nantes-Saint-Herblain); Bruno Levy (Hôpital Central Nancy, Nancy); Alexandre Mebazaa (Hôpital Lariboisière, Paris); Gilles Montalescot (Hôpital Pitié-Salpêtrière, Paris); Gérald Roul (Hôpital de Hautepierre, Strasbourg); Rémi Sabatier (CHU Côte de Nacre, Caen); Pierre Squara (Clinique Ambroise Paré, Neuilly sur Seine); Gabriel Steg (Hôpital Bichat-Claude Bernard, Paris); Jean-Louis Teboul (CHU Bicêtre, Le Kremlin-Bicetre); Paul Touboul (Hôpital Cardiologique Louis Pradel, Bron); Philippe Vignon (Hôpital Dupuytren, Limoges); Simon Weber (Hôpital Cochin Port Royal, Paris); Faies Zannad (CHU de Nancy, Vandoeuvre les Nancy); Robin Zelinsky (Clinique Saint-Sauveur, Mulhouse). Germany: Gerhard Bauriedel (Universitätsklinikum Bonn, Bonn); Michael Böhm (Universitätskliniken des Saarlandes, Homburg/Saar); Michael Buerke (Klinikum der Medizinischen Fakultät der Martin-Luther-Universität Halle-Wittenberg, Halle [Saale]); Angelika Costard-Jäckle (AK St Georg, Hamburg); Aly El-Banayosy (Herz-u Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen); Gerd Hasenfub (Universitätsklinikum Göttingen, Göttingen); Franz Xaver Kleber (Unfallkrankenhaus Berlin, Berlin); Veselin Mitrovic (Kerckhoff Klinik GmbH, Bad Nauheim); Thomas Münzel (Universitätsklinikum Hamburg-Eppendorf, Hamburg); Klaus Pethig (Klinik für Innere Medizin III der Friedrich Schiller Universität Jena, Jena); Andrew Remppis (Medizinische Universitätsklinik und Poliklinik, Heidelberg); Peter Schuster (St Marien Krankenhaus Siegen, Siegen); Robert Schwinger (Universität zu Köln, Köln [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 People's Friendship University, Moscow); Mikhail Y. Ruda (Russian Cardiology Research Centre, Moscow); Raisa I. Stryuk, Sergey N. Tereschenko, and Vladimir S. Zadionchenko (Moscow 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 George's 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 Delgado-Herrera 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.

REFERENCES
1.
Cuffe MS, Califf RM, Adams KF Jr.  et al.  Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial.  JAMA. 2002;287:1541-1547PubMedArticle
2.
Bayram M, De Luca L, Massie MB, Gheorghiade M. Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes.  Am J Cardiol. 2005;96:(6A)  47G-58GPubMedArticle
3.
Haikala H, Kaivola J, Nissinen E, Wall P, Levijoki J, Linden IB. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan.  J Mol Cell Cardiol. 1995;27:1859-1866PubMedArticle
4.
Pollesello P, Ovaska M, Kaivola J.  et al.  Binding of a new Ca2+ sensitizer, levosimendan, to recombinant human cardiac troponin C: a molecular modelling, fluorescence probe, and proton nuclear magnetic resonance study.  J Biol Chem. 1994;269:28584-28590PubMed
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;333:249-259PubMedArticle
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;90:5-11PubMedArticle
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;36:1903-1912PubMedArticle
8.
Slawsky MT, Colucci WS, Gottlieb SS.  et al.  Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure.  Circulation. 2000;102:2222-2227PubMedArticle
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;23:1422-1432PubMedArticle
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;34:536-546PubMedArticle
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;98:74-78PubMedArticle
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;360:196-202PubMedArticle
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;287:1531-1540PubMedArticle
15.
O'Connor 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;11:200-205PubMedArticle
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;8:697-705PubMedArticle
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 meta-regression analysis.  Eur J Heart Fail. 2002;4:515-529PubMedArticle
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;293:1900-1905PubMedArticle
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;40:465-471PubMed
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;27:2725-2736PubMedArticle
21.
Metra M, Nodari S, D'Aloia 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;40:1248-1258PubMedArticle
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;81:141-149PubMedArticle
23.
Bódi 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;22:313-327PubMed
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