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Levosimendan Improves Renal Function in Patients With Advanced Chronic Heart Failure Awaiting Cardiac Transplantation
Journal of Cardiac Failure Vol. 13 No. 6 2007
Clinical Trial
Levosimendan Improves Renal Function in Patients With Advanced Chronic Heart Failure Awaiting Cardiac Transplantation GREGOR ZEMLJIC, MD,1 MATJAZ BUNC, MD, PhD,1 ARIA P. YAZDANBAKHSH, MD,2 AND BOJAN VRTOVEC, MD, PhD1 Ljubljana, Slovenia; Amsterdam, The Netherlands
ABSTRACT Background: Long-term impact of levosimendan on renal function remains undefined. Prospectively, we evaluated effects of levosimendan on renal function in patients with advanced chronic heart failure awaiting cardiac transplantation. Methods and Results: Of 40 patients, 20 were randomized to receive levosimendan (10-minute bolus 12 mg/kg, followed by 0.1 mg/kg/min for 24 hours; LS Group), and 20 received no levosimendan (Controls). The groups did not differ in age, heart failure etiology, left ventricular ejection fraction, and plasma brain natriuretic peptide. Patients were followed for 3 months. At baseline, the groups did not differ in serum creatinine (1.92 6 0.13 mg/dL in LS Group versus 1.91 6 0.12 mg/dL in Controls, P 5 .81) and creatinine clearance (43.7 6 2.9 mL/min versus 43.9 6 2.8 mL/min, P 5 .84). At 3 months, we found a decrease in serum creatinine and an increase in creatinine clearance in LS Group, but not in Controls, leading to a significant intergroup difference in serum creatinine (1.60 6 0.26 mg/dL in LS Group versus 1.90 6 0.14 mg/dL in Controls, P 5 .005) and creatinine clearance (53.6 6 8.6 mL/min versus 44.0 6 3.3 mL/ min, P 5 .005). An improvement in creatinine $0.5 mg/dL occurred in 50% patients from LS Group compared with 10% of Controls (P 5 .005). Conclusions: Levosimendan improves long-term renal function in advanced chronic heart failure patients awaiting cardiac transplantation. (J Cardiac Fail 2007;13:417e421) Key Words: Heart failure, renal function, heart transplantation.
Renal insufficiency has emerged as a critical risk factor for mortality in patients with heart failure, with impaired renal function conferring nearly twice the risk for death and hospitalization.1 Impaired renal function was independently associated with an increased risk for death, cardiovascular death, and hospitalization for heart failure in a broad spectrum of patients with chronic heart failure in the CHARM study.2 In advanced chronic heart failure,
renal impairment has been shown to be a stronger predictor of mortality than either left ventricular ejection fraction or New York Heart Association (NYHA) class.3 In cardiac transplant recipients, the risk of developing posttransplant chronic renal insufficiency is strongly related to preoperative serum creatinine concentration. Patients with preoperative serum creatinine O1.5 mg/dL were shown to have up to 3-fold increased risk of chronic renal insufficiency during 5-year posttransplant period compared with patients with creatinine !1.5 mg/dL.4 Furthermore, impaired pretransplant renal function defined as creatinine clearance !40 mL/min has been associated with higher early and late posttransplant mortality.5 Therefore, interventions improving renal function in patients with advanced heart failure could potentially improve both pretransplant and posttransplant survival in this patient cohort. Levosimendan is a novel calcium-sensitizing agent that was shown in 1 trial to offer a survival benefit over
From the 1Advanced Heart Failure and Transplantation Center, Division of Cardiology, Ljubljana University Medical Center, Ljubljana, Slovenia and 2Department of Cardiothoracic Surgery, University of Amsterdam, Amsterdam, The Netherlands. Manuscript received September 13, 2006; revised manuscript received February 24, 2007; revised manuscript accepted March 7, 2007. Reprint requests: Bojan Vrtovec, MD, PhD, Division of Cardiology, Ljubljana University Medical Center, Zaloska 7, Ljubljana, Slovenia. MC SI-1000, Ljubljana. 1071-9164/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2007.03.005
417
418 Journal of Cardiac Failure Vol. 13 No. 6 August 2007 dobutamine in low cardiac output decompensated heart failure.6 However, the recent randomized trials failed to show a correlation between hemodynamic efficacy of the drug and sustained survival benefit.7 This suggests that parameters other than improved cardiac hemodynamics may be of importance in determining the outcomes of levosimendantreated patients. Although levosimendan infusion was associated with short-term decreases of serum creatinine in the Levosimendan Compared with Dobutamine in Severe LowOutput Heart Failure (LIDO) study,6 the duration of its effect on renal function remains undefined. Therefore, the aim of this study was to better define the long-term impact of single levosimendan infusion on renal function in patients with advanced chronic heart failure. Because renal function is of particular importance in patients awaiting heart transplantation,5 the principal goal of the study was to test whether or not levosimendan improves renal function in this patient cohort. Methods
variables were made by chi-square test. Parameters reaching or approaching statistical significance in the univariate analysis were included in the multivariate regression model for prediction of improvement in renal function. A value of P ! .05 was considered significant.
Results Patient Characteristics
Baseline patient characteristics are presented in Table 1. The 2 groups did not differ in age, heart failure etiology, heart rate, QTc interval, sodium, left ventricular ejection fraction, or plasma brain natriuretic peptide (BNP) levels. All of the patients survived the follow-up period, and none underwent heart transplantation or implantation of a left ventricular assist device. After 3 months, we found an improvement in left ventricular ejection fraction in the LS Group, but not in Controls (Fig. 1). Similarly, we found a decrease in plasma BNP levels only in patients who received levosimendan (Fig. 2).
Patient Population
Levosimendan and Renal Function
In a prospective trial, we enrolled 40 consecutive patients with advanced chronic heart failure who were referred for cardiac transplantation listing at Advanced Heart Failure and Transplantation Program, Ljubljana University Medical Center. All patients were NYHA Class III or IV class heart failure for at least 3 months before referral, and were treated with optimal medical therapy at maximally tolerated doses according to the latest guidelines.8 Before listing, all patients were screened according to the standard protocol to satisfy all of the cardiac transplantation listing criteria.9 Informed consent was obtained in all patients before participation in the study, and the study protocol was approved by the National Medical Ethics Committee.
At baseline, the 2 groups had comparable renal function as indicated by serum creatinine concentration (1.92 6 0.13 mg/dL in LS Group versus 1.91 6 0.12 mg/dL in Controls, P 5 .81) and creatinine clearance calculated by CockroftGault equation (43.7 6 2.9 mL/min in LS Group versus 43.9 6 2.8 mL/min in Controls, P 5 .84). After 1 month, we found a decrease in creatinine in LS Group (e0.32 6 0.28 mg/dL, P 5 .005), but not in Controls (e0.01 6 0.13 mg/dL, P 5 .93); this difference persisted throughout the 3-month study period (Fig. 3). A similar trend was observed when calculating creatinine clearance (Fig. 4). Consequently, at 3 months, the 2 groups differed significantly in serum creatinine (1.60 6 0.26 mg/dL in LS Group versus 1.90 6 0.14 mg/dL in Controls, P 5 .005) and creatinine clearance (53.6 6 8.6 mL/min in LS Group versus 44.0 6 3.3 mL/min in Controls, P 5 .005). A significant
Study Design At the time of evaluation, 20 patients (LS Group) were randomized to receive levosimendan (10-minute bolus with 12 mg/kg, followed by 0.1 mg$kg$min for 24 hours), and the remaining 20 received no levosimendan infusion (Controls). Twenty-four hours after levosimendan infusion, all of the patients were discharged and followed regularly for 3 months in the Heart Failure/Transplant Clinic. In all patients, we measured serum creatinine concentrations before levosimendan infusions, and at monthly intervals up to 3 months. Significant change of renal function was defined as a change in plasma creatinine of at least 0.5 mg/dL.10,11 All of the patients received optimal medical therapy at maximally tolerated doses before entering the study. The study protocol did not allow for introduction of any additional therapies during the 3-month follow-up. Therefore, as seen in Table 2, the treatment regimens remained virtually unchanged both in the LS and Control groups. Statistical Analysis Continuous variables were expressed as mean 6 SD. Differences between the groups and the time-dependent changes were analyzed by means of 1-factor analysis of variance followed by Tukey’s test for continuous variables. Comparisons of categoric
Table 1. Baseline Patient Characteristics
Age (y) Gender Male Female Etiology Ischemic Nonischemic NYHA class IV Heart rate, beats/min QT interval, ms BNP, pg/mL LVEF, % Sodium, mmol/L
Levosimendan-Treated Patients (n 5 20)
Control Group (n 5 20)
P
53 6 12
54 6 11
.31
19 (95) 1 (5)
18 (90) 2 (10)
.55
11 (55) 9 (45) 20 (100) 78 6 14 476 6 30 792 6 425 28 6 18 133 6 4
14 (70) 6 (30) 20 (100) 81 6 12 481 6 25 771 6 421 27 6 17 134 6 5
.33 1 .66 .77 .81 .54 .76
Results are presented as mean 6 SD or number of patients (%). NYHA, New York Heart Association; BNP, brain natriuretic peptide; LVEF, left ventricular ejection fraction.
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Table 2. Treatment Regimen of the Patients Treated With Levosimendan (LS Group) and in the Control Group (Controls) Baseline LS Group (n 5 20) Loop diuretics Spironolactone Angiotensin-converting enzyme inhibitors AT-blockers b-blockers Digoxin
20 10 18 2 15 3
3 Months
Controls (n 5 20)
(100) (50) (90) (10) (75) (15)
20 13 17 3 16 2
(100) (65) (85) (15) (80) (10)
P 1 0.34 0.63 0.63 0.70 0.63
LS Group (n 5 20) 19 10 17 3 15 3
Controls (n 5 20)
(95) (50) (90) (15) (75) (15)
20 13 18 2 16 2
(100) (65) (90) (10) (80) (10)
P 1 .34 .63 .63 .70 .63
Results are presented as number of patients (%).
improvement in renal function (improvement in creatinine by at least 0.5 mg/dL) occurred in 50% of patients from LS Group compared with 10% of Controls (P 5 .005) (Fig. 5). Multivariate Analysis
The results of univariate and multivariate analysis for prediction of improvement in renal function by at least 0.5 mg/dL are presented in Table 3. Levosimendan therapy, improvement in left ventricular ejection fraction, and decrease in plasma BNP were predictive of renal function improvement on univariate analysis. However, on multivariate analysis, levosimendan therapy was the only independent predictor of renal function improvement at 3 months. Discussion This is the first study to date evaluating the long-term effects of levosimendan on renal function in patients with advanced heart failure listed for heart transplantation. In these patients, a 24-hour levosimendan infusion was associated
with a significant improvement in renal function 1 month after therapy, with its effect persisting up to 3 months. This suggests that levosimendan may exert a sustained beneficial effect on renal function in advanced heart failure. In patients with severe heart failure, levosimendan causes rapid dose-dependent improvement in hemodynamic function.12 Maximal hemodynamic effects of levosimendan have been shown to occur 1 to 3 days after starting the infusion and are sustained for at least a week.13 Furthermore, an improvement in left ventricular ejection fraction seems to persist up to 90 days after infusion, suggesting a prolonged hemodynamic effect of the drug.14 In accordance with these findings, we found a trend toward an improved left ventricular performance 3 months after levosimendan infusion, as seen by an increase left ventricular ejection fraction and a decrease in plasma BNP. Both parameters were related to improvement in renal function on univariate analysis, suggesting that improved hemodynamics and increased kidney perfusion could represent an important mechanism leading to better renal function in patients receiving levosimendan. 1300
60 P=0.05
P=0.62
P=0.04*
Baseline 50
3 months
P=0.71 Baseline 3 months
1200 1100 1000
BNP [pg/ml]
LVEF [%]
40
30
20
900 800 700 600 500
10
400 0
300 Levosimendantreated patients
Controls
Fig. 1. Changes in left ventricular ejection fraction in patients with and without significant improvement in renal function at 3 months.
Levosimendantreated patients
Controls
Fig. 2. Changes in plasma brain natriuretic protein levels in patients with and without significant improvement in renal function at 3 months.
420 Journal of Cardiac Failure Vol. 13 No. 6 August 2007 2,40
Levosimendan
1,80
*
1,60
*
*
1,40 1,20
Controls
Levosimendan
1,00 Baseline
1 month
2 months
3 months
Time
2,4
2,4
2,2
2,2
Creatinine [mg/dl]
2,00
Creatinine [mg/dl]
Creatinine [mg/dl]
2,20
2 1,8 1,6 1,4
Creatinine Clearance [ml/min]
1,8 1,6 1,4
1
1 Baseline
However, in multivariate analysis, levosimendan therapy was shown to predict improved renal function independently from changes in left ventricular performance. This suggests that factors other than improved hemodynamics may be responsible for changes in renal function observed in this study. Data on the effects of levosimendan on renal function are few and controversial, mostly based on the observations in animal models of sepsis. Pagel et al15 showed that levosimendan increases renal medullary blood flow and decreases cortical blood flow in normal dogs, whereas Oldner et al16 showed no change in renal blood flow in a very early phase of sepsis. Faivre et al17 confirmed the absence of effects of levosimendan on both macrocirculation and microcirculation in septic animals despite a marked improvement in cardiac output. However, in the study of Zager et al,18 levosimendan conferred almost complete protection against experimental endotoxemic (lipopolysaccharide-induced) acute renal failure, which likely stems from its vasoactive properties. In the LIDO study,6 levosimendan improved renal function over 24 hours (mean change in creatinine concentration e0.10 mg/dL), whereas dobutamine did not (e0.011 mg/dL, P 5 .03 for the comparison with levosimendan). In our study levosimendan therapy was associated
2
1,2
1,2
Fig. 3. Changes in plasma creatinine concentration in patients treated with levosimendan and in the control group.
Controls
3 months
Baseline
3 months
Fig. 5. Plasma creatinine concentration at baseline and after 3 months in patients treated with levosimendan and in the control group.
with a sustained improvement of renal function with the decline in serum creatinine being similar to the one observed in the LIDO trial. This suggests that the early renoprotective effects of levosimendan may be present for a prolonged period. The underlying mechanisms of potential renoprotective effects of levosimendan remain undefined. Through its metabolite, OR-1896, levosimendan has been shown to have a prolonged positive inotropic effect on ventricular myocardium and vasodilatory effect on vasculature.19 Both improved cardiac output and vasodilatation, could lead to better renal perfusion and improved kidney function. Alternatively, Parissis et al20 have reported that levosimendan improves the inflammatory status of patients hospitalized for severe heart failure; namely, it reduces the serum levels of interleukin-6, soluble Fas, and soluble Fas ligand. Because inflammation is an important determinant of renal dysfunction in advanced heart failure,21 the renoprotective effects of levosimendan could also partly result from its anti-inflammatory activity.
70
*
*
*
60
Table 3. Univariate and Multivariate Predictors of Improved Renal Function at 3 Months (Defined as a Decline in Serum Creatinine O0.5 mg/dL)
50
Univariate Multivariate P
40 30 Levosimendan
Controls
20 Baseline
1 month
2 months
3 months
Time
Fig. 4. Changes in creatinine clearance in patients treated with levosimendan and in the control group.
Levosimendan therapy Increase in LVEF Decrease in plasma BNP Ischemic heart failure etiology
Beta
95% Confidence Interval 0.05e0.77
P
0.005*
0.45
.026*
0.048* 0.044*
0.07 0.11
0.30e0.42 0.43e0.21
.73 .50
0.078
0.21
0.28e0.32
.13
LVEF, left ventricular ejection fraction; BNP, brain natriuretic protein. *P ! .05.
Levosimendan and Kidneys in Heart Failure Limitations of the Study
Our study and its findings have several limitations. The study cohort was small and the treatment unblinded. We assessed renal function only by measuring serum creatinine and creatinine clearance, both of which could be affected by factors other than levosimendan. To minimize our measurement error, fluid balance and the doses of other therapies were tightly controlled throughout the study period. Also, our study was not designed to adequately address potential noncardiac effects of the drug, which may have been partly responsible for improved renal function observed in this study. Conclusions The results of this study suggest that levosimendan exerts beneficial effects on renal function in patients with advanced chronic heart failure. Although the effects are modest, they appear to persist up to 3 months after the infusion. Further studies are needed to better define the underlying mechanisms and to determine whether or not the levosimendan-related improvement in renal function offers a survival benefit in this patient cohort. Acknowledgments The authors would like to thank Andreja Briski for coordinating the study and for her dedicated assistance throughout the study period.
References 1. Smith GL, Shlipak MG, Havranek EP, et al. Race and renal impairment in heart failure: Mortality in black versus whites. Circulation 2005;111:1270e7. 2. Hillege HL, Nitsch D, Pfeffer MA, et al, on behalf of the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) investigators. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006; 113:671e8. 3. Hillege HL, Girbes ARJ, de Kam PJ, et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation 2000;102:203e10. 4. Vossler MR, Ni H, Toy W, Hershberger RE. Pre-operative renal function predicts development of chronic renal insufficiency after orthotopic heart transplantation. J Heart Lung Transplant 2002;21:874e81. 5. Odim J, Wheat J, Laks H, et al. Peri-operative renal function and outcome after orthotopic heart transplantation. J Heart Lung Transplant 2006;25:162e6.
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6. 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;360:196e202. 7. Cleland JG, Freemantle N, Coletta AP, et al. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail 2006;8:105e10. 8. Swedberg K, Cleland J, Dargie H, et al. Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005;26:1115e40. 9. Costanzo MR, Augustine S, Bourge R, et al. Selection and treatment of candidates for heart transplantation. A statement for health professionals from the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation 1995;92:3593e612. 10. Gottlieb SS, Abraham W, Butler J, et al. The prognostic importance of different definitions of WRF in congestive heart failure. J Card Fail 2002;8:136e41. 11. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of WRF with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111:1487e91. 12. Slawsky MT, Colucci WS, Gottlieb SS, et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators. Circulation 2000;102:2222e7. 13. Lilleberg J, Laine M, Palkama T, Kivikko M, Pohjanjousi P, Kupari M. Duration of the haemodynamic action of a 24-h infusion of levosimendan in patients with congestive heart failure. Eur J Heart Fail 2007;9: 75e82. 14. McLean AS, Huang SJ, Nalos M, Ting I. Duration of the beneficial effects of levosimendan in decompensated heart failure as measured by echocardiographic indices and B-type natriuretic peptide. J Cardiovasc Pharmacol 2005;46:830e5. 15. Pagel P, Hettrick D, Warltier D. Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs. Br J Pharmacol 1996;119:609e15. 16. Oldner A, Konrad D, Weitzberg E, Rudehill A, Rossi P, Wanecek M. Effects of levosimendan, a novel inotropic calciumsensitizing drug, in experimental septic shock. Crit Care Med 2001;29:2185e93. 17. Faivre V, Kaskos H, Callebert J, et al. Cardiac and renal effects of levosimendan, arginine vasopressin, and norepinephrine in lipopolysaccharide-treated rabbits. Anesthesiology 2005;103:514e21. 18. Zager RA, Johnson AC, Lund S, Hanson SY, Abrass CK. Levosimendan protects against experimental endotoxemic acute renal failure. Am J Physiol Renal Physiol 2006;290:F1453e62. 19. Kivikko M, Lehtonen L. Levosimendan: a new inodilatory drug for the treatment of decompensated heart failure. Curr Pharm Des 2005;11: 435e55. 20. Parissis JT, Adamopoulos S, Antoniades C, et al. Effects of levosimendan on circulating pro-inflammatory cytokines and soluble apoptosis mediators in patients with decompensated advanced heart failure. Am J Cardiol 2004;93:1309e12. 21. Shlipak MG, Fried LF, Crump C, et al. Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation 2003;107:87e92.
Clinical Trial
Levosimendan Improves Renal Function in Patients With Advanced Chronic Heart Failure Awaiting Cardiac Transplantation GREGOR ZEMLJIC, MD,1 MATJAZ BUNC, MD, PhD,1 ARIA P. YAZDANBAKHSH, MD,2 AND BOJAN VRTOVEC, MD, PhD1 Ljubljana, Slovenia; Amsterdam, The Netherlands
ABSTRACT Background: Long-term impact of levosimendan on renal function remains undefined. Prospectively, we evaluated effects of levosimendan on renal function in patients with advanced chronic heart failure awaiting cardiac transplantation. Methods and Results: Of 40 patients, 20 were randomized to receive levosimendan (10-minute bolus 12 mg/kg, followed by 0.1 mg/kg/min for 24 hours; LS Group), and 20 received no levosimendan (Controls). The groups did not differ in age, heart failure etiology, left ventricular ejection fraction, and plasma brain natriuretic peptide. Patients were followed for 3 months. At baseline, the groups did not differ in serum creatinine (1.92 6 0.13 mg/dL in LS Group versus 1.91 6 0.12 mg/dL in Controls, P 5 .81) and creatinine clearance (43.7 6 2.9 mL/min versus 43.9 6 2.8 mL/min, P 5 .84). At 3 months, we found a decrease in serum creatinine and an increase in creatinine clearance in LS Group, but not in Controls, leading to a significant intergroup difference in serum creatinine (1.60 6 0.26 mg/dL in LS Group versus 1.90 6 0.14 mg/dL in Controls, P 5 .005) and creatinine clearance (53.6 6 8.6 mL/min versus 44.0 6 3.3 mL/ min, P 5 .005). An improvement in creatinine $0.5 mg/dL occurred in 50% patients from LS Group compared with 10% of Controls (P 5 .005). Conclusions: Levosimendan improves long-term renal function in advanced chronic heart failure patients awaiting cardiac transplantation. (J Cardiac Fail 2007;13:417e421) Key Words: Heart failure, renal function, heart transplantation.
Renal insufficiency has emerged as a critical risk factor for mortality in patients with heart failure, with impaired renal function conferring nearly twice the risk for death and hospitalization.1 Impaired renal function was independently associated with an increased risk for death, cardiovascular death, and hospitalization for heart failure in a broad spectrum of patients with chronic heart failure in the CHARM study.2 In advanced chronic heart failure,
renal impairment has been shown to be a stronger predictor of mortality than either left ventricular ejection fraction or New York Heart Association (NYHA) class.3 In cardiac transplant recipients, the risk of developing posttransplant chronic renal insufficiency is strongly related to preoperative serum creatinine concentration. Patients with preoperative serum creatinine O1.5 mg/dL were shown to have up to 3-fold increased risk of chronic renal insufficiency during 5-year posttransplant period compared with patients with creatinine !1.5 mg/dL.4 Furthermore, impaired pretransplant renal function defined as creatinine clearance !40 mL/min has been associated with higher early and late posttransplant mortality.5 Therefore, interventions improving renal function in patients with advanced heart failure could potentially improve both pretransplant and posttransplant survival in this patient cohort. Levosimendan is a novel calcium-sensitizing agent that was shown in 1 trial to offer a survival benefit over
From the 1Advanced Heart Failure and Transplantation Center, Division of Cardiology, Ljubljana University Medical Center, Ljubljana, Slovenia and 2Department of Cardiothoracic Surgery, University of Amsterdam, Amsterdam, The Netherlands. Manuscript received September 13, 2006; revised manuscript received February 24, 2007; revised manuscript accepted March 7, 2007. Reprint requests: Bojan Vrtovec, MD, PhD, Division of Cardiology, Ljubljana University Medical Center, Zaloska 7, Ljubljana, Slovenia. MC SI-1000, Ljubljana. 1071-9164/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2007.03.005
417
418 Journal of Cardiac Failure Vol. 13 No. 6 August 2007 dobutamine in low cardiac output decompensated heart failure.6 However, the recent randomized trials failed to show a correlation between hemodynamic efficacy of the drug and sustained survival benefit.7 This suggests that parameters other than improved cardiac hemodynamics may be of importance in determining the outcomes of levosimendantreated patients. Although levosimendan infusion was associated with short-term decreases of serum creatinine in the Levosimendan Compared with Dobutamine in Severe LowOutput Heart Failure (LIDO) study,6 the duration of its effect on renal function remains undefined. Therefore, the aim of this study was to better define the long-term impact of single levosimendan infusion on renal function in patients with advanced chronic heart failure. Because renal function is of particular importance in patients awaiting heart transplantation,5 the principal goal of the study was to test whether or not levosimendan improves renal function in this patient cohort. Methods
variables were made by chi-square test. Parameters reaching or approaching statistical significance in the univariate analysis were included in the multivariate regression model for prediction of improvement in renal function. A value of P ! .05 was considered significant.
Results Patient Characteristics
Baseline patient characteristics are presented in Table 1. The 2 groups did not differ in age, heart failure etiology, heart rate, QTc interval, sodium, left ventricular ejection fraction, or plasma brain natriuretic peptide (BNP) levels. All of the patients survived the follow-up period, and none underwent heart transplantation or implantation of a left ventricular assist device. After 3 months, we found an improvement in left ventricular ejection fraction in the LS Group, but not in Controls (Fig. 1). Similarly, we found a decrease in plasma BNP levels only in patients who received levosimendan (Fig. 2).
Patient Population
Levosimendan and Renal Function
In a prospective trial, we enrolled 40 consecutive patients with advanced chronic heart failure who were referred for cardiac transplantation listing at Advanced Heart Failure and Transplantation Program, Ljubljana University Medical Center. All patients were NYHA Class III or IV class heart failure for at least 3 months before referral, and were treated with optimal medical therapy at maximally tolerated doses according to the latest guidelines.8 Before listing, all patients were screened according to the standard protocol to satisfy all of the cardiac transplantation listing criteria.9 Informed consent was obtained in all patients before participation in the study, and the study protocol was approved by the National Medical Ethics Committee.
At baseline, the 2 groups had comparable renal function as indicated by serum creatinine concentration (1.92 6 0.13 mg/dL in LS Group versus 1.91 6 0.12 mg/dL in Controls, P 5 .81) and creatinine clearance calculated by CockroftGault equation (43.7 6 2.9 mL/min in LS Group versus 43.9 6 2.8 mL/min in Controls, P 5 .84). After 1 month, we found a decrease in creatinine in LS Group (e0.32 6 0.28 mg/dL, P 5 .005), but not in Controls (e0.01 6 0.13 mg/dL, P 5 .93); this difference persisted throughout the 3-month study period (Fig. 3). A similar trend was observed when calculating creatinine clearance (Fig. 4). Consequently, at 3 months, the 2 groups differed significantly in serum creatinine (1.60 6 0.26 mg/dL in LS Group versus 1.90 6 0.14 mg/dL in Controls, P 5 .005) and creatinine clearance (53.6 6 8.6 mL/min in LS Group versus 44.0 6 3.3 mL/min in Controls, P 5 .005). A significant
Study Design At the time of evaluation, 20 patients (LS Group) were randomized to receive levosimendan (10-minute bolus with 12 mg/kg, followed by 0.1 mg$kg$min for 24 hours), and the remaining 20 received no levosimendan infusion (Controls). Twenty-four hours after levosimendan infusion, all of the patients were discharged and followed regularly for 3 months in the Heart Failure/Transplant Clinic. In all patients, we measured serum creatinine concentrations before levosimendan infusions, and at monthly intervals up to 3 months. Significant change of renal function was defined as a change in plasma creatinine of at least 0.5 mg/dL.10,11 All of the patients received optimal medical therapy at maximally tolerated doses before entering the study. The study protocol did not allow for introduction of any additional therapies during the 3-month follow-up. Therefore, as seen in Table 2, the treatment regimens remained virtually unchanged both in the LS and Control groups. Statistical Analysis Continuous variables were expressed as mean 6 SD. Differences between the groups and the time-dependent changes were analyzed by means of 1-factor analysis of variance followed by Tukey’s test for continuous variables. Comparisons of categoric
Table 1. Baseline Patient Characteristics
Age (y) Gender Male Female Etiology Ischemic Nonischemic NYHA class IV Heart rate, beats/min QT interval, ms BNP, pg/mL LVEF, % Sodium, mmol/L
Levosimendan-Treated Patients (n 5 20)
Control Group (n 5 20)
P
53 6 12
54 6 11
.31
19 (95) 1 (5)
18 (90) 2 (10)
.55
11 (55) 9 (45) 20 (100) 78 6 14 476 6 30 792 6 425 28 6 18 133 6 4
14 (70) 6 (30) 20 (100) 81 6 12 481 6 25 771 6 421 27 6 17 134 6 5
.33 1 .66 .77 .81 .54 .76
Results are presented as mean 6 SD or number of patients (%). NYHA, New York Heart Association; BNP, brain natriuretic peptide; LVEF, left ventricular ejection fraction.
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Table 2. Treatment Regimen of the Patients Treated With Levosimendan (LS Group) and in the Control Group (Controls) Baseline LS Group (n 5 20) Loop diuretics Spironolactone Angiotensin-converting enzyme inhibitors AT-blockers b-blockers Digoxin
20 10 18 2 15 3
3 Months
Controls (n 5 20)
(100) (50) (90) (10) (75) (15)
20 13 17 3 16 2
(100) (65) (85) (15) (80) (10)
P 1 0.34 0.63 0.63 0.70 0.63
LS Group (n 5 20) 19 10 17 3 15 3
Controls (n 5 20)
(95) (50) (90) (15) (75) (15)
20 13 18 2 16 2
(100) (65) (90) (10) (80) (10)
P 1 .34 .63 .63 .70 .63
Results are presented as number of patients (%).
improvement in renal function (improvement in creatinine by at least 0.5 mg/dL) occurred in 50% of patients from LS Group compared with 10% of Controls (P 5 .005) (Fig. 5). Multivariate Analysis
The results of univariate and multivariate analysis for prediction of improvement in renal function by at least 0.5 mg/dL are presented in Table 3. Levosimendan therapy, improvement in left ventricular ejection fraction, and decrease in plasma BNP were predictive of renal function improvement on univariate analysis. However, on multivariate analysis, levosimendan therapy was the only independent predictor of renal function improvement at 3 months. Discussion This is the first study to date evaluating the long-term effects of levosimendan on renal function in patients with advanced heart failure listed for heart transplantation. In these patients, a 24-hour levosimendan infusion was associated
with a significant improvement in renal function 1 month after therapy, with its effect persisting up to 3 months. This suggests that levosimendan may exert a sustained beneficial effect on renal function in advanced heart failure. In patients with severe heart failure, levosimendan causes rapid dose-dependent improvement in hemodynamic function.12 Maximal hemodynamic effects of levosimendan have been shown to occur 1 to 3 days after starting the infusion and are sustained for at least a week.13 Furthermore, an improvement in left ventricular ejection fraction seems to persist up to 90 days after infusion, suggesting a prolonged hemodynamic effect of the drug.14 In accordance with these findings, we found a trend toward an improved left ventricular performance 3 months after levosimendan infusion, as seen by an increase left ventricular ejection fraction and a decrease in plasma BNP. Both parameters were related to improvement in renal function on univariate analysis, suggesting that improved hemodynamics and increased kidney perfusion could represent an important mechanism leading to better renal function in patients receiving levosimendan. 1300
60 P=0.05
P=0.62
P=0.04*
Baseline 50
3 months
P=0.71 Baseline 3 months
1200 1100 1000
BNP [pg/ml]
LVEF [%]
40
30
20
900 800 700 600 500
10
400 0
300 Levosimendantreated patients
Controls
Fig. 1. Changes in left ventricular ejection fraction in patients with and without significant improvement in renal function at 3 months.
Levosimendantreated patients
Controls
Fig. 2. Changes in plasma brain natriuretic protein levels in patients with and without significant improvement in renal function at 3 months.
420 Journal of Cardiac Failure Vol. 13 No. 6 August 2007 2,40
Levosimendan
1,80
*
1,60
*
*
1,40 1,20
Controls
Levosimendan
1,00 Baseline
1 month
2 months
3 months
Time
2,4
2,4
2,2
2,2
Creatinine [mg/dl]
2,00
Creatinine [mg/dl]
Creatinine [mg/dl]
2,20
2 1,8 1,6 1,4
Creatinine Clearance [ml/min]
1,8 1,6 1,4
1
1 Baseline
However, in multivariate analysis, levosimendan therapy was shown to predict improved renal function independently from changes in left ventricular performance. This suggests that factors other than improved hemodynamics may be responsible for changes in renal function observed in this study. Data on the effects of levosimendan on renal function are few and controversial, mostly based on the observations in animal models of sepsis. Pagel et al15 showed that levosimendan increases renal medullary blood flow and decreases cortical blood flow in normal dogs, whereas Oldner et al16 showed no change in renal blood flow in a very early phase of sepsis. Faivre et al17 confirmed the absence of effects of levosimendan on both macrocirculation and microcirculation in septic animals despite a marked improvement in cardiac output. However, in the study of Zager et al,18 levosimendan conferred almost complete protection against experimental endotoxemic (lipopolysaccharide-induced) acute renal failure, which likely stems from its vasoactive properties. In the LIDO study,6 levosimendan improved renal function over 24 hours (mean change in creatinine concentration e0.10 mg/dL), whereas dobutamine did not (e0.011 mg/dL, P 5 .03 for the comparison with levosimendan). In our study levosimendan therapy was associated
2
1,2
1,2
Fig. 3. Changes in plasma creatinine concentration in patients treated with levosimendan and in the control group.
Controls
3 months
Baseline
3 months
Fig. 5. Plasma creatinine concentration at baseline and after 3 months in patients treated with levosimendan and in the control group.
with a sustained improvement of renal function with the decline in serum creatinine being similar to the one observed in the LIDO trial. This suggests that the early renoprotective effects of levosimendan may be present for a prolonged period. The underlying mechanisms of potential renoprotective effects of levosimendan remain undefined. Through its metabolite, OR-1896, levosimendan has been shown to have a prolonged positive inotropic effect on ventricular myocardium and vasodilatory effect on vasculature.19 Both improved cardiac output and vasodilatation, could lead to better renal perfusion and improved kidney function. Alternatively, Parissis et al20 have reported that levosimendan improves the inflammatory status of patients hospitalized for severe heart failure; namely, it reduces the serum levels of interleukin-6, soluble Fas, and soluble Fas ligand. Because inflammation is an important determinant of renal dysfunction in advanced heart failure,21 the renoprotective effects of levosimendan could also partly result from its anti-inflammatory activity.
70
*
*
*
60
Table 3. Univariate and Multivariate Predictors of Improved Renal Function at 3 Months (Defined as a Decline in Serum Creatinine O0.5 mg/dL)
50
Univariate Multivariate P
40 30 Levosimendan
Controls
20 Baseline
1 month
2 months
3 months
Time
Fig. 4. Changes in creatinine clearance in patients treated with levosimendan and in the control group.
Levosimendan therapy Increase in LVEF Decrease in plasma BNP Ischemic heart failure etiology
Beta
95% Confidence Interval 0.05e0.77
P
0.005*
0.45
.026*
0.048* 0.044*
0.07 0.11
0.30e0.42 0.43e0.21
.73 .50
0.078
0.21
0.28e0.32
.13
LVEF, left ventricular ejection fraction; BNP, brain natriuretic protein. *P ! .05.
Levosimendan and Kidneys in Heart Failure Limitations of the Study
Our study and its findings have several limitations. The study cohort was small and the treatment unblinded. We assessed renal function only by measuring serum creatinine and creatinine clearance, both of which could be affected by factors other than levosimendan. To minimize our measurement error, fluid balance and the doses of other therapies were tightly controlled throughout the study period. Also, our study was not designed to adequately address potential noncardiac effects of the drug, which may have been partly responsible for improved renal function observed in this study. Conclusions The results of this study suggest that levosimendan exerts beneficial effects on renal function in patients with advanced chronic heart failure. Although the effects are modest, they appear to persist up to 3 months after the infusion. Further studies are needed to better define the underlying mechanisms and to determine whether or not the levosimendan-related improvement in renal function offers a survival benefit in this patient cohort. Acknowledgments The authors would like to thank Andreja Briski for coordinating the study and for her dedicated assistance throughout the study period.
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