ORIGINAL RESEARCH ARTICLE

Effect of Levosimendan on Estimated Glomerular Filtration Ratein Hospitalized Patients with Decompensated Heart Failure andRenal Dysfunction

Zhi-Qiang Hou,1 Zhao-Xia Sun,2 Chong-Yi Su,1 Hui Tan,1 Xia Zhong,1 Bo Hu,1 Yi Zhou1 & De-Ya Shang1

1 Emergency Department, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China

2 Department of Cardiology, 2nd People’s Hospital of Jinan, Jinan, China

Keywords

B-type Natriuretic peptide; Decompensated

heart failure; Estimated glomerular filtration

rate; Levosimendan; Placebo; Renal

dysfunction.

Correspondence

De-Ya Shang, Emergency Department,

Shandong Provincial Hospital Affiliated to

Shandong University, 324, Jing Wu Road,

Jinan Shandong 250021, China.

Tel.: 86-0531-85187513;

Fax: 86-0531-85187513;

E-mail: hzqdaifu@163.com

doi: 10.1111/1755-5922.12001

SUMMARY

Background: Only limited data of the long-term effect of levosimendan on renal dysfunc-

tion in patients with decompensated heart failure (DHF) have been published previously.

To date, there has been no similar study carried out in a Chinese population. Design and

Methods: A prospective, randomized, placebo-controlled, and double-blind study was per-

formed to investigate the effect of levosimendan on estimated glomerular filtration rate

(eGFR) in DHF patients with renal dysfunction during a 30-day period. Sixty-six patients

with left ventricular ejection fraction (LVEF) �40% and eGFR 15–89 mL/min/1.73 m2

were randomized in a 1:1 ratio to receive a 24-h infusion with levosimendan or placebo.

The B-type natriuretic peptide (BNP) and eGFR were determined at baseline and day 1, 3,

7, 14, 30 after the start of treatment. Results: The eGFR levels were obviously enhanced

following levosimendan, peaked at 3 days, sustained for at least 14 days, and returned to

baseline by day 30 after starting infusion. In contrast, placebo did not induce any significant

changes in eGFR levels during the follow-up. In addition, levosimendan resulted in a dis-

tinct decrease in BNP levels in comparison with placebo, and the beneficial effect returned

to baseline by day 14 and remained so at day 30 postinfusion. Conclusions: A 24-h infu-

sion with levosimendan transiently improved the renal dysfunction compared with placebo

in patients with DHF, and its beneficial effects persisted for at least 14 days after the initia-

tion of treatment.

Introduction

As one of the most important comorbidities of heart failure,

renal dysfunction has emerged as a critical risk factor for pro-

longed hospitalization, readmission, and short- and long-term

mortality in patients with decompensated heart failure (DHF)

[1,2]. The association of renal insufficiency with DHF leading

to the so-called cardiorenal syndrome (CRS) has received

increasing attention [3]. Unfortunately, the clinical manage-

ment of CRS is largely empiric, and many traditional drugs for

heart failure may result in the impairment of renal function

because of inappropriate or excessive utilization or their serious

side effects [4].

Levosimendan, a novel inotropic and vasodilatory agent, has

been developed for the treatment of DHF and is used intrave-

nously when patients with heart failure require immediate ini-

tiation of drug therapy. The positive inotropic action of

levosimendan occurs as a result of the calcium-dependent bind-

ing to cardiac troponin C, while its vasodilative effect is mainly

due to the opening of ATP-sensitive potassium channels in vas-

cular smooth muscle [5,6]. To date, several clinical trials have

already been preformed to verify the hemodynamic and clinical

effects of levosimendan in patients with heart failure, and com-

parison with other standard inotropic agents, such as dobuta-

mine [7–10]. In the Levosimendan Infusion versus Dobutamine

(LIDO) study, levosimendan treatment was associated with a

significant increase in cardiac output and decrease in pulmo-

nary capillary wedge pressure, as well as an obvious decrease

in mortality in patients with severe heart failure, compared

with dobutamine [7]. However, only limited studies evaluating

the potential effects of levosimendan on renal dysfunction in

hospitalized patients with DHF have been previously published,

especially the long-term effects [7,11,12]. In a recent study, it

has reported the improvement in renal function after a 24-h

administration of levosimendan was observed at 1 month and

persisted for up to 3 months in patients with advanced chronic

heart failure awaiting cardiac transplantation [12]. However,

whether those findings obtained in the above-mentioned study

are also generalized in the Chinese heart failure population

remains unknown.

Therefore, this study was conducted to evaluate the effect of a

single 24-h infusion with levosimendan on estimated glomerular

filtration rate (eGFR) in hospitalized patients with DHF and renal

dysfunction during a 30-day follow-up.

108 Cardiovascular Therapeutics 31 (2013) 108–114 ª 2012 Blackwell Publishing Ltd

Methods

Study Population

In this prospective, randomized, placebo-controlled, and double-

blind study, the study population consists of consecutive patients

who admitted to our hospital between April 2010 and August

2011 with a diagnosis of DHF (as documented by the presence of

pulmonary or systemic congestion or symptoms and signs of low

cardiac output, despite maximally tolerated oral therapy), age over

18 years, New York Heart Association (NYHA) functional class III–

IV, left ventricular ejection fraction (LVEF) � 40% by echocardio-

graphic examinations and eGFR 15–89 mL/min/1.73 m2.

Criteria for exclusion were a systolic blood pressure (BP)

<90 mmHg in supine position, benign or life-threatening tachyar-

rhythmias, myocardial infarction or coronary revascularization

within the previous 3 months, pulmonary embolism, hypertro-

phic cardiomyopathy, evidence if noncardiovascular factors as

main cause of symptoms, history of renal diseases such as diabetic

nephropathy, hypertension nephropathy, glomerulonephritis,

autoimmune nephrosis, nephrotic syndrome, invasive examina-

tion requiring contrast administration or taking nephrotoxic

medicines within the preceding 3 months and during the hospi-

talization, requiring dialysis and ultrafiltration for symptom relief,

significant liver damage (liver transaminases three times above

the upper normal limit) and/or liver failure (prothrombin time

3-seconds above the upper normal limit in the absence of antico-

agulant therapy), electrolytic abnormalities, hypersensitivity to

levosimendan or any of its excipients.

The investigation conforms with the principles outlined in the

Declaration of Helsinki. The study protocol was reviewed and

approved by the Hospital Ethics Committee, and all patients gave

their informed consent.

Study Protocol

Within 24 h after admission, all enrolled patients were random-

ized (sealed opaque envelopes) in a 1:1 ratio to receive either

levosimendan or placebo (water-soluble vitamin 10 mL diluted in

500 mL of glucose 5%). Study drug administration was initiated

with an optional loading dose of 12 lg/kg of levosimendan or

placebo for 10 min, and this was followed by a continuous infusion

of 0.05 lg/kg/min, 0.1 lg/kg/min or 0.2 lg/kg/min of levosimen-

dan for 24 h, via a peripheral or central vein. The decision to

administer or withhold the loading dose and the choice of the

maintenance dose were at the discretion of the investigators,

based on their clinical assessment of the patients. An initial main-

tenance dose of 0.1 lg/kg/min was suggested; if after 30–60 min

the response was considered excessive, because of the occurrence

of tachycardia or hypotension, it was suggested that the dose be

reduced to 0.05 lg/kg/min; if the effects persisted, the drug could

be discontinued; If the initial maintenance dose was well tolerated

and a greater hemodynamic effect was desired, increasing to

0.2 lg/kg/min could be considered [13]. During the infusions, the

diuretic dose remained unchanged, and no change in the intrave-

nous fluid administration was allowed.

The baseline evaluation (before starting levosimendan)

included the medical history, physical examination, heart rate,

noninvasive assessment of systolic BP and diastolic BP, 24-h

urinary output and blood samples for assessment of B-type

natriuretic peptide (BNP), serum creatinine (SCr), and cystatin

C (CysC). At the end of 24-h infusion, patients underwent

assessment of clinical symptoms and signs, heart rate, BP, and

24-h urinary output. Furthermore, parameters of renal function

and BNP levels were repeatedly measured at 1, 3, 7, 14,

30 days after the administration of levosimendan in the whole

study group.

Laboratory Examination

All blood analyses were carried out in the central laboratory of

our hospital. SCr was detected using conventional methods with

an Olympus AU5400 (Olympus, Tokyo, Japan) automated clinical

biochemistry analyzer. CysC was measured by means of the im-

munonephelometric assay with an Olympus AU5400 (Olympus)

automated clinical biochemistry analyzer. BNP assay was per-

formed with the electrochemiluminescence immunoassay-based

Cobas E601 System (Roche Diagnostics, Tokyo, Japan).

Calculation of eGFR

Regardless of well-known limitations, the simplified Modification

of Diet in Renal Disease (MDRD) equation using four variables for

eGFR has gained widespread acceptance and recommendation

[14], and it is calculated as follows:

eGFR1ðmL=min=1:73 m2Þ ¼ 186:3� ðSCr�1:154Þ � ðage�0:203Þ� 1:212 ðif blackÞ � 0:742 ðif femaleÞ

(1)

Recently, a new CysC-based equation developed by Macisaac

et al. [15] appeared to provide more precise GFR estimation in the

Chinese patients with mild to moderate kidney impairment [16],

and it is calculated as follows:

eGFR2ðmL=min=1:73 m2Þ ¼ ð86:7=SCrÞ � 4:2 (2)

In this study, eGFR was determined using these two equations

above mentioned.

Statistical Analysis

Data were summarized using mean, standard error, numbers, and

percentages, as appropriate. Baseline characteristics were assessed

using the chi-squared test for dichotomous variables and indepen-

dent samples t-test for continuous variables. A repeated-measures

general linear model (GLM) using group, time, and group and

time interaction as within-subject factors was used to compare the

effects on eGFR and BNP. Bonferroni correction for multiple com-

parisons of post hoc analyses and Greenhouse–Geisser correction

of degrees of freedom were applied as required. An analysis of

covariance (ANCOVA) was utilized to compare the changes in

eGFR and BNP from baseline over time (1 day, 3, 7, 14, 30 days

after the initiation of treatment) between placebo and levosimen-

dan group with the baseline values as covariates. All statistical

analyses were performed using SPSS 19.0 (SPSS Inc., Chicago, IL,

USA). Statistical significance was defined as P < 0.05.

ª 2012 Blackwell Publishing Ltd Cardiovascular Therapeutics 31 (2013) 108–114 109

Z.-Q. Hou et al. Effect of Levosimendan

Results

Patients

A total of 70 patients were recruited into the study. Two patients

(one in the placebo group and one in the levosimendan group)

who self-discharged or transferred to other local hospitals or com-

munity health centers during admission were excluded from all

analyses. One patient in the L group had a drug withdrawal

because of hypotension and new tachyarrhythmia during the lev-

osimendan infusion. One patient in the placebo group underwent

the percutaneous coronary intervention with stenting for acute

ST-segment–elevation myocardial infarction within 24 h of

admission. Thus, these two patients were not included in this

study. Finally, 66 enrolled patients (33 in the placebo group and

33 in the levosimendan group) were evaluated.

As shown in Table 1, there were no significant differences

between two groups with respect to general characteristics,

prehospital treatment, hemodynamic parameters, urine output,

cardiac and renal function at baseline, and the cumulative

dosages of diuretics and other drugs (all P > 0.05). In addition, the

maintenance dose of levosimendan was 0.05 lg/kg/min in 22%,

0.1 lg/kg/min in 74%, and 0.2 lg/kg/min in 13% of the patients

in levosimendan group.

Changes in Blood Pressure, Heart Rate, andUrine Output after a 24-h Infusion

As shown in Table 1, the mean systolic BP at baseline was

121 ± 5 mmHg in the placebo and 121 ± 7 mmHg in the levosim-

endan group. There was a noticeable decrease from baseline sys-

tolic BP in the levosimendan group during the first 24 h

(P < 0.05). Mean diastolic BP at baseline was 70 ± 9 mmHg in the

placebo and 72 ± 8 mmHg in the levosimendan group. The

changes from baseline in diastolic BP after a 24 h-infusion were

small in both study groups (P > 0.05). In terms of heart rate, a

slight but not significant increase was observed during levosimen-

dan infusion (P > 0.05). Besides, 24-h urine output increased

from the pre-infusion mean level of 1024.8 ± 265.2 mL to

1898.7 ± 481.1 mL at 24 h after infusion in the levosimendan

group and from 1038.0 ± 188.7 mL to 1843.3 ± 553.8 mL in the

placebo group (both P < 0.05).

Changes in eGFR during a 30-day Follow-up

As shown in Table 2, baseline levels of eGFR1 were similar in

the levosimendan to placebo group (P > 0.05). Levosimendan

significantly increased eGFR1 levels by about 22% (P < 0.05) at

day 1, by 73% (P < 0.05) at day 3, by 64% (P < 0.05) at day

7, and by 43% (P < 0.05) at day 14 after starting treatment.

The eGFR1 levels reached their highest value at day 3 and

returned almost to the baseline levels by 30 days postinfusion

(increased by 7.1%, P > 0.05) in patients treated with levosim-

endan. On the contrary, placebo infusion resulted in only an

insignificant increase in eGFR1, peaking at day 7 and returning

to baseline levels by 30 days (Figure 1A). Furthermore, com-

parison between groups at each time point indicated levosimen-

dan led to a greater change in eGFR1 from baseline than

placebo at 1, 3, 7, and 14 days, whereas no significant differ-

ences were obtained at 30 days after the initiation of infusion

(Figure 1C).

Table 1 Baseline characteristics of the study population

Placebo

group

(n = 33)

Levosimendan

group

(n = 33) P-value

Age (years) 72.5 ± 8.1 74.4 ± 5.0 0.38

Sex (female/male) 17/16 16/17 0.77

Body weight (kg) 66.7 ± 7.8 68.6 ± 8.7 0.43

Prehospital treatment (n)

ACEI or ARB 30 31 0.64

Loop diuretics 33 33 1.00

Spironolactone 12 16 0.12

Digoxin 24 23 0.77

Beta-blockers 27 30 0.23

Nitrates 18 20 0.55

Systolic BP

pre-infusion (mmHg)

121.0 ± 5.0 121.0 ± 7.0 0.47

Diastolic BP

pre-infusion (mmHg)

70.0 ± 9.0 72.0 ± 8.0 0.15

Systolic BP

postinfusion (mmHg)

119.0 ± 7.0 115.0 ± 10.0 0.09

Diastolic BP

postinfusion (mmHg)

68.0 ± 7.0 71.0 ± 9.0 0.24

HR pre-infusion

(beats/min)

82.0 ± 11.0 81.0 ± 11.0 0.88

HR postinfusion

(beats/min)

81.0 ± 9.0 83.0 ± 8.0 0.48

24-h urine output

pre-infusion (mL)

1038.0 ± 188.7 1024.8 ± 265.2 0.85

24-h urine output

postinfusion (mL)

1843.3 ± 553.8 1898.7 ± 481.1 0.71

Baseline cardiac function

NYHA class (III/IV) 19/14 18/15 0.77

BNP (pg/mL) 1507.2 ± 429.9 1501.7 ± 403.7 0.80

LVEF (%) 33.6 ± 2.9 32.7 ± 3.6 0.21

Baseline renal function

SCr (lmol/L) 144.9 ± 33.4 147.1 ± 32.2 0.82

CysC (mg/L) 1.9 ± 0.5 1.9 ± 0.4 0.87

eGFR1 (mL/min/1.73 m2) 40.4 ± 12.6 39.4 ± 11.2 0.80

eGFR2 (mL/min/1.73 m2) 42.6 ± 10.1 42.8 ± 9.4 0.95

Cumulative dosages (mg/kg)

ACEI 5.9 ± 1.9 (7) 5.5 ± 2.3 (12) 0.71

ARB 31.7 ± 6.8 (16) 31.1 ± 6.0 (21) 0.82

Loop diuretics 17.7 ± 2.8 17.5 ± 3.1 0.81

Spironolactone 13.5 ± 2.4 13.0 ± 3.2 0.52

Digoxin 0.065 ± 0.015 0.065 ± 0.009 0.95

Beta-blockers 7.5 ± 1.3 7.1 ± 1.4 0.30

Nitrates 3.5 ± 0.8 3.2 ± 0.9 0.28

N, number; ACEI, angiotensin-converting enzyme inhibitor; ARB, angioten-

sin receptor blocker; HR, heart rate; BP, blood pressure; NYHA, New York

Heart Association; BNP, B-type natriuretic peptide; LVEF, left ventricular

ejection fraction; SCr, serum creatinine; CysC, cystatin C; eGFR1, estimated

glomerular filtration rate calculated using the equation (1); eGFR2,

estimated glomerular filtration rate calculated using the equation (2). Data

of age, body weight, BNP, LVEF, and baseline measurements were shown

as mean ± SD. Statistical significance was defined as P < 0.05.

110 Cardiovascular Therapeutics 31 (2013) 108–114 ª 2012 Blackwell Publishing Ltd

Effect of Levosimendan Z.-Q. Hou et al.

Baseline levels of eGFR2 were parallel in patients of levosimen-

dan group with placebo group (P > 0.05). Similarly, eGFR2 levels

were notably elevated in response to levosimendan by about

18.2% (P < 0.05) at day 1, by 66.8% (P < 0.05) at day 3, by

56.5% (P < 0.05) at day 7, and by 45.6% (P < 0.05) at day 14,

and then gradually slid to the baseline levels at day 30 postinfu-

sion (increased by 8.6%, P > 0.05). In contrast, in the placebo

group eGFR2 levels slightly fluctuated during a 30-day follow-up

(Table 2 and Figure 1B). There were significant differences in

changes in eGFR2 from baseline between levosimendan and

placebo group at day 1–14 after the initiation of treatment

(Figure 1D).

Changes in BNP during a 30-day Follow-up

Mean baseline values for BNP were 1501.7 ± 502.7 pg/mL in the

levosimendan and 1507.2 ± 429.9 pg/mL in the placebo group.

BNP levels decreased significantly in response to levosimendan at

day 1, touched the bottom at day 3, sprang back to the pre-infu-

sion levels by 14 days, and remained so by 30 days. However,

there was an almost horizontal trend in BNP levels in patients of

the placebo group over the analysis period (Figure 2A). Till day 7,

a significantly greater decrease of BNP levels from baseline in

response to levosimendan than placebo was observed. However,

there were no significant differences in changes in BNP levels

Table 2 Mean eGFR and BNP in patients of levosimendan and placebo group during the 30-day study period

Parameter Baseline 1 day 3 day 7 day 14 day 30 day

Overall P

Time

Time 9

group

eGFR1 (mL/min/1.73 m2)

Placebo (n = 33) 40.4 ± 12.6 39.6 ± 11.5 42.4 ± 11.3 43.2 ± 10.8 43.0 ± 11.8 41.2 ± 10.6 <0.001 <0.001

Levosimendan (n = 33) 39.4 ± 11.2 47.9 ± 13.4 68.3 ± 14.9 64.8 ± 15.6 57.3 ± 11.7 42.2 ± 11.1

eGFR2 (mL/min/1.73 m2)

Placebo (n = 33) 42.6 ± 10.1 43.7 ± 9.8 47.7 ± 11.1 49.6 ± 12.4 49.4 ± 9.5 45.8 ± 8.2 <0.001 <0.001

Levosimendan (n = 33) 42.8 ± 9.4 50.6 ± 11.5 71.4 ± 12.4 66.7 ± 14.1 62.3 ± 12.0 46.5 ± 9.4

BNP (pg/mL)

Placebo (n = 33) 1507.2 ± 429.9 1500.9 ± 428.2 1432.6 ± 397.6 1412.4 ± 334.4 1429.3 ± 353.5 1462.3 ± 376.2 <0.001 <0.001

Levosimendan (n = 33) 1501.7 ± 502.7 1109.5 ± 328.9 896.7 ± 236.1 1078.4 ± 322.3 1417.4 ± 403.2 1435.3 ± 433.5

N, number; eGFR1, estimated glomerular filtration rate calculated using the equation (1); eGFR2, estimated glomerular filtration rate calculated using

the equation (2); BNP, B-type natriuretic peptide. All data are expressed as mean ± SD.

Figure 1 Mean eGFR1 (A) and eGFR2 (B) at baseline and day 1, 3, 7, 14, 30 after the start of treatment, as well as changes in eGFR1 (C) and eGFR2 (D) from

baseline over time in placebo and levosimendan group. eGFR1, estimated glomerular filtration rate calculated using the equation (1); eGFR2, estimated

glomerular filtration rate calculated using the equation (2). Data are expressed as mean ± SD. *Statistically significant difference compared with baseline

within group (P < 0.05); **Statistically significant difference between placebo and levosimendan (P < 0.05).

ª 2012 Blackwell Publishing Ltd Cardiovascular Therapeutics 31 (2013) 108–114 111

Z.-Q. Hou et al. Effect of Levosimendan

from baseline between two study drugs at day 14 and 30 postinfu-

sion (Figure 2B).

Discussion

The present study showed that a 24-h levosimendan infusion was

associated with a significant and transient enhancement of eGFR

levels in patients with DHF and renal dysfunction, with its favor-

able effect persisting for at least 14 days after the start of therapy.

Levosimendan is a positive inotropic drug with vasodilating

properties that have been extensively investigated in various

experimental studies and clinical trials. However, imperfect infor-

mation about the potential effect of levosimendan on renal func-

tion in patients with DHF has been obtained. In the LIDO trial, a

short-term reduction of SCr levels induced by levosimendan infu-

sion was observed [7]. Recently, another study reported that a 24-

h infusion with levosimendan significantly increased the eGFR

levels (calculated by MDRD formula) by about 45.5% at 72 h

postinfusion in patients with congestive heart failure [11].

In accordance with these previous data, our study showed that

levosimendan infusion caused a rapid and obvious improvement

in either eGFR1 or eGFR2 compared with baseline values in

patients with DHF and renal dysfunction (mean change 73–78%)

at day 3 after starting treatment. It suggested levosimendan could

have a short-term beneficial effect on renal function in patients

with DHF.

To further investigate the long-term renal impact of levosimen-

dan, we repeatedly assessed the eGFR levels at day 7, 14, and 30

postinfusion. We found the favorable improvement in renal func-

tion induced by levosimendan sustained for at least 14 days,

whereas disappeared by 30 days after the initiation of treatment.

However, Zemljic G and colleagues reported that the creatinine

clearance levels were significantly elevated at 1 month and per-

sisted up to 3 months after 24-h administration of levosimendan

in patients with advanced chronic heart failure awaiting cardiac

transplantation [12]. In our opinion, there may be several poten-

tial reasons for the differences in obtained outcomes. First of all,

the substantial differences in patients’ populations between two

studies may be one of the most important influencing factors. For

an example, the pharmacokinetics of intravenous levosimendan

in Asia is different from Caucasian patients owing to the polymor-

phic distribution of N-acetyltransferase in the populations [5].On

the other hand, levosimendan has a short half-life (about 1.5 h),

so its prolonged actions (about 7–9 days) are mainly due to its

active metabolite OR-1896 that has an approximately 80 h half-

life and exhibits hemodynamic effects similar to the parent drug

in patients with heart failure [6,17–19]. Furthermore, Puttonen J

et al. found the half-life of OR-1896 was prolonged 1.5-fold

(96.5 ± 19.5 h) in patients with severe chronic renal failure (cre-

atinine clearance <30 mL/min/1.73 m2) and end-stage renal

disease undergoing hemodialysis as compared with healthy

subjects (61.6 ± 5.2 h) [20]. However, the mean eGFR levels at

baseline in patients enrolled in this analysis were more than

30 mL/min/1.73 m2. Moreover, the excretion of OR-1896 may be

accelerated because of the amelioration of renal function after lev-

osimendan infusion. Recent studies indicated that levosimendan

transiently improved the cardiac out, right ventricular systolic

function, and plasma BNP, and the effects sustained for at least

7 days, returned to baseline by day 30 postinfusion, and remained

so on day 90 in patients with DHF [21,22]. Similarly, in our study,

plasma BNP levels also displayed a pattern of temporary improve-

ment in response to levosimendan infusion, which may provide

another indirect evidence. In addition, the sample sizes of two

studies are both relatively small, which may also potentially result

in the differences.

The mechanisms underlying renal protective actions of levosim-

endan in patients with DHF are not yet fully understood. These

possibly include the following: first, levosimendan causes periph-

eral arterial and venous dilation by opening the ATP-sensitive K+

(KATP) channel in vascular smooth muscle cells, which may

contribute to augmentation of renal perfusion and depression of

central venous pressure [11,23,24]. Second, levosimendan

improves cardiac output through its inotropic actions, which leads

to an increment in renal blood flow [5,6,25]. Third, levosimendan

may block ANG-II-mediated mesangial cell contraction with con-

sequent increase in glomerular capillary surface area and GFR

[26]. Moreover, a single-dose levosimendan administration seems

to have anti-inflammatory and anti-apoptotic properties, reducing

circulating proinflammatory cytokines and soluble apoptosis

mediators [27]. In addition, it was reported that levosimendan

could significantly reduce renal ischemia–reperfusion injury in a

rabbit model [28].

Figure 2 Mean BNP levels (A) at baseline and day 1, 3, 7, 14, 30 after the

start of treatment and changes in BNP (B) from baseline over time in

placebo and levosimendan group. BNP, B-type natriuretic peptide. Data

are expressed as mean ± SD. *Statistically significant difference

compared with baseline within group (P < 0.05); **Statistically significant

difference between placebo and levosimendan (P < 0.05).

112 Cardiovascular Therapeutics 31 (2013) 108–114 ª 2012 Blackwell Publishing Ltd

Effect of Levosimendan Z.-Q. Hou et al.

Numerous studies have demonstrated that renal dysfunction is

common in patients hospitalized for heart failure and appears to

be associated with adverse in-hospital and postdischarge outcomes

[1,2,29]. Moreover, worsening renal function, although transient,

is associated with longer hospitalization and with a higher risk of

death and readmission in patients with acute heart failure [29].

Therefore, in our opinion, the transient improvement of renal

function induced by levosimendan may at least contribute to the

standard management for heart failure, as well as decreasing the

length of hospital stay and in-hospital cost.

Several limitations of our study should be considered. First, this

was a single-center research with relatively small sample size. A

larger sample of patients from multiple centers would make the

analysis more robust and objective. Second, we did not directly

measure the GFR by specific tracers, such as inulin and iothala-

mate, which are not commonly carried out in the laboratory of

our hospital. Third, those hospitalized DHF patients with normal

renal function (eGFR � 90 mL/min/1.73 m2) or renal failure

(eGFR <15 mL/min/1.73 m2) were not enrolled into this analysis,

so we could not assess the comprehensive effects of levosimendan

on renal function in patients with DHF.

Conclusions

The results of this study suggest that a 24-h infusion with levosim-

endan provides significant improvement in renal dysfunction

compared with placebo in patients with DHF, and its favorable

renoprotective effect is transient.

Acknowledgments

I would like to acknowledge with deep gratitude the assistance

and guidance given to me by all my colleagues in the Emergency

Department. A special acknowledgment should be shown to Pro-

fessor De-Ya Shang for his suggestions and encouragement.

Finally, I wish to extend my thanks to my family for their endless

love and selfless support.

Conflict of Interest

The authors declare no conflict of interest.

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