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European Journal of Heart Failure 2005 7(7):1156-1163; doi:10.1016/j.ejheart.2005.05.001
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© 2005 European Society of Cardiology

Short-term effects of levosimendan and prostaglandin E1 on hemodynamic parameters and B-type natriuretic peptide levels in patients with decompensated chronic heart failure

Deddo Moertl*, Rudolf Berger, Martin Huelsmann, Anja Bojic and Richard Pacher1

Department of Cardiology, Medical University of Vienna Waehringer Guertel 18-20, A-1090 Vienna, Austria

* Corresponding author. Tel.: +43 1 40400 4614; fax: +43 1 4081148. E-mail address: deddo_moertl{at}yahoo.de


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Both levosimendan and prostaglandin E1 (PGE1) have beneficial effects on hemodynamic parameters and outcome compared to dobutamine in decompensated chronic heart failure (CHF).

Aims: We compared short-term effects of levosimendan versus PGE1 on hemodynamic parameters and B-type natriuretic peptide levels (BNP) in patients with decompensated CHF.

Methods and results: 73 patients (cardiac index <2.5 L/min/m2 pulmonary capillary wedge pressure (PCP)> 15 mmHg) with decompensated CHF were randomised to treatment with either a 24 h-infusion of levosimendan (n=38) or a chronic infusion of PGE1 (n=35). Hemodynamic parameters and BNP were measured at baseline, 24 and 48 h, BNP levels were also measured after 1 week. Baseline characteristics including concomitant medication were similar in both groups. Levosimendan and PGE1 increased cardiac output (CO) after 24 and 48 h. Levosimendan increased CO twice as much as PGE1 (24 h: Levosimendan +1.1±0.1 L/min, PGE1 +0.6±0.1 L/min, p>0.001). Both drugs produced a comparable reduction in PCP and pulmonary artery pressure after 24 and 48 h. Levosimendan decreased BNP by 28% after 24 h and 22% after 48 h, but effects disappeared after 1 week. In contrast, PGE1 decreased BNP by 15% after 48 h (no change at 24 h), but a decrease of 20% was sustained at 1 week.

Conclusions: The differential beneficial effects of levosimendan (greater increase in CO) and PGE1 (sustained decrease in BNP) may have a potential impact on clinical outcome.

Key Words: Levosimendan • Prostaglandin E1 • B-type natriuretic peptide • Decompensated heart failure • Hemodynamic • Cardiac output

Received March 29, 2004; Revised September 8, 2004; Accepted May 5, 2005


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Short-term use of intravenous catecholamines and phosphodiesterase III inhibitors is a common practice to stabilise patients with decompensated heart failure [1]. However, there is no evidence that these agents improve outcome [2]. In fact, use of intravenous milrinone in patients with ischemic heart failure [3] showed worsened outcome, which has been attributed to an increase in diastolic intracellular calcium levels [4] leading to impaired diastolic relaxation [5], increased myocardial oxygen consumption [6] and malignant tachyarrhythmias due to calcium overload [7].

The inodilator levosimendan has pharmacological and hemodynamic advantages over conventional intravenous inotropic agents. Levosimendan has positive inotropic effects based on calcium sensitization of the cardiac myofilaments [8] and does not increase intracellular calcium levels [9]. Therefore, levosimendan does not impair ventricular diastolic relaxation [10], does not increase myocardial oxygen consumption [11] and has a low risk of triggering malignant tachyarrhythmias [12]. Levosimendan also has vasodilatory effects based on opening of ATP-sensitive potassium channels [13]. These inotropic and vasodilatory effects increase cardiac output, lower filling pressures and decrease systemic and pulmonary vascular resistance, leading to an improvement in hemodynamic status and outcome compared to dobutamine in patients with severe low-output heart failure [14–16].

Besides inotropic agents, intravenous vasodilators such as sodium-nitroprusside and nitroglycerin are commonly used in patients with decompensated heart failure. They primarily decrease ventricular filling pressures and systemic vascular resistance by vasodilation and as a result indirectly increase cardiac output. The use of intravenous vasodilators in decompensated heart failure is supported by data showing that decreases in left ventricular filling pressures are correlated with improved symptoms and survival [17]. However, continuous intravenous administration of nitroglycerin or sodium-nitroprusside is limited by the rapid development of tolerance or toxic effects.

The vasodilator prostaglandin E1 has shown neither development of tolerance nor toxicity during long-term intravenous treatment [18]. Similar to levosimendan, prostaglandin E1 has beneficial hemodynamic effects as compared to dobutamine in patients with severe heart failure. Intravenous prostaglandin E1 also increases cardiac output and lowers filling pressures and systemic and pulmonary vascular resistance [19]. Furthermore, continuous infusion of prostaglandin E1 improves clinical outcome compared to dobutamine in patients with end-stage heart failure [20]. These beneficial effects of prostaglandin E1 can be attributed to the favourable hemodynamic effects and not triggering arrhythmias, properties that are similar to levosimendan. Furthermore, prostaglandin E1 exhibits angiogenetic effects in human myocardium and less cardiac fibrosis has been found in patients chronically treated with prostaglandin E1 [21]. Moreover, antiproliferatory effects of prostaglandins inhibit pulmonary vascular remodelling, which might contribute to the survival benefits in pulmonary hypertensive patients [22]. These properties make prostaglandin E1 an ideal drug for the short-term clinical stabilization of patients with decompensated chronic heart failure with the potential for long-term treatment of these patients.

Therefore, levosimendan and PGE1 are both beneficial treatments for the short-term therapy of decompensated heart failure and both improve hemodynamic status and clinical outcome compared to dobutamine. However, to date there are no data available to decide which drug should be preferred.

Short-term therapeutic goals in decompensated chronic heart failure are generally an improvement in hemodynamic status. A decrease in pulmonary artery wedge pressure has been shown to be associated with a survival benefit [17], which makes this parameter a primary treatment target in decompensated heart failure. B-type natriuretic peptide is one of the best prognostic markers in heart failure [23,24], and especially in patients with decompensated chronic heart failure, changes in B-type natriuretic peptide levels during treatment have been shown to be strong predictors for mortality and early readmission [25].

In this study we therefore evaluated the short-term effects of levosimendan and prostaglandin E1 on hemodynamic parameters and B-type natriuretic peptide levels in patients with decompensated chronic heart failure.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study design, inclusion and exclusion criteria
This prospective randomized study was designed to compare the short-term changes in hemodynamic parameters and B-type natriuretic peptide levels, induced by a levosimendan infusion over 24 h or continuous intravenous prostaglandin E1 infusion.

Patients admitted to our heart failure unit with a diagnosis of decompensated chronic heart failure despite optimized conventional treatment and who were judged to require hemodynamic monitoring and intravenous support were eligible to participate in the study. Inclusion criteria were age 18–85 years, New York Heart Association class IIIb or IV, left ventricular ejection fraction <35% by radionuclide ventriculography within the previous 3 months, pulmonary capillary wedge pressure >15 mmHg, cardiac index <2.5 L/min/m2, B-type natriuretic peptide >400 pg/ml or N-terminal atrial natriuretic peptide >6300 fmol/ml [26,27]. Exclusion criteria were a systolic blood pressure <90 mmHg in supine position, serum creatinine >2.5 mg/dl, severe obstructive pulmonary disease, myocardial infarction or coronary revascularization within the previous 3 months, hypertrophic cardiomyopathy, severe obstructive valvular disease, pre-existing intravenous positive inotropic support, or known adverse reactions to either study drug.

The study complied with the Declaration of Helsinki, the protocol was approved by the institutional ethics committee and all patients gave written informed consent prior to study participation.

2.2. Study drugs
2.2.1. Levosimendan
Levosimendan, administered to the recommended dose range, produces a therapeutically active metabolite (OR-1896) with an elimination half-life of 70–80 h, this metabolite produces hemodynamic effects similar to that of levosimendan. Therefore, the effects of levosimendan last up to 7–9 days after discontinuation of a 24 h levosimendan infusion [28], this makes continuation or reinfusion of levosimendan within 1 week unnecessary and possibly even harmful due to potential accumulation. Currently an infusion duration of 24 h is recommended and the beneficial hemodynamic effects of 24 h infusion and 24 h after discontinuation are well documented [16].

2.2.2. Prostaglandin E1
Prostaglandin E1 is a short-acting substance with short-acting metabolites [29], continuous infusion is therefore necessary to achieve sustained effects. Over the last 10 years we have used a side-effect-guided up-titration for individual dose-finding for prostaglandin E1 therapy. However, in our experience prostaglandin side-effects lead to dose reduction to <5 ng/kg/min in most patients within 4 weeks with further decreases during the following months [20]. Thus, in this study for reasons of feasibility and to prevent side effects we did not perform up-titration and started with a fixed dose of 2.5 ng/kg/min prostaglandin E1.

2.3. Protocol
Patients were randomized to either levosimendan infusion over 24 h or continuous prostaglandin E1 infusion. Hemodynamic parameters were measured at least 2 h after the insertion of a Swan–Ganz catheter (=baseline) and then 24 and 48 h after the start of the infusion. Intravenous infusions of the study drugs were given via a central venous line and started only if the patient had a blood pressure ≥90 mmHg. Levosimendan (Simdax, Orion Pharma, Finland) was given at an infusion rate of 0.1 µg/kg/min for 24 h and Prostaglandin E1 (Alprostapint, Pint Pharma, Austria) was given at a dose of 2.5 ng/kg/min for 7 days. If the patient had a blood pressure of ≥95 mmHg, initial loading doses were: Levosimendan 12 µg/kg for 10 min or Prostaglandin E1 10 ng/kg/min for 10min. Peripheral arterial blood pressure was recorded as follows: at the beginning of the infusion, after 5, 10, 15, and 30 min, and after 1, 2, 3, 6, 12, 18, 24, and 48 h. This schedule was restarted after each change in dose. If blood pressure was ≥85 mmHg but <90 mmHg, the infusion rates were halved. If blood pressure was <85 mmHg, the study drugs were stopped. If the blood pressure recovered within 30 min, infusions were restarted at half dosage, if not, the study drugs were withdrawn. At least 1000 ml/d crystalloids were given to prevent hypovolemia under intravenous vasodilator therapy. Routine laboratory parameters were checked on a daily basis within the first 48 h and after 1 week. Except for diuretics, concomitant medication was kept constant during the first 48 h. To enable hospital discharge, PGE1-patients received a Hickmann catheter via the supraclavian approach after the last hemodynamic measurement and PGE1 was administered by an ambulatory infusion pump (CADD-1, Phamacia Deltec, St. Paul, Minnesota, USA). Therefore, patients in both groups were equally mobilized after 48 h.

2.4. Hemodynamic assessment
Heart rate was measured using continuous monitor-ECG, peripheral artery blood pressure was measured non-invasively. Cardiac output (thermodilution technique), central venous pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure were measured via Swan–Ganz catheter. Stroke volume and systemic and pulmonary vascular resistance were derived from hemodynamic measurements.

2.5. Measurement of natriuretic peptides
Blood samples for analysis of natriuretic peptide levels were drawn with the patient in a supine position immediately before the hemodynamic measurements (baseline, 24 and 48 h) and after 1 week. Natriuretic peptide levels were determined by Enzyme-Linked Immunosorbent Assay (B-type natriuretic peptide: Biosite Diagnostics, USA; N-terminal atrial natriuretic peptide: Biomedica, Austria) by an observer that was blinded to patient identity and treatment allocation.

2.6. Statistical analysis
Data are expressed as mean±standard error of mean. Data were analysed using Fisher's exact test and Student's t-test for paired and unpaired data where appropriate. A value of p<0.05 was considered statistically significant.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Patients
75 patients were recruited into the study. One patient in the levosimendan group had a drug-withdrawal due to hypotension, in error no more data were recorded and thus the patient was excluded from all analyses. One patient in the prostaglandin E1 group had his beta-blocker therapy increased after 24 h. This was classified as a protocol violation and the patient was excluded from all analyses. Thus, a total of 73 patients, 38 in the levosimendan group and 35 in the prostaglandin E1 group, were analysed.

No significant differences between treatment groups were noted as regards patient characteristics, conventional heart failure treatment, laboratory parameters (Table 1), or hemodynamic parameters at baseline (Table 2).


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  		Table 1 Baseline demographics, clinical characteristics, and concomitant drugs

 


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  		Table 2 Change in hemodynamic parameters

 
3.2. Hemodynamic effects
Both 24 h infusion of levosimendan and continuous infusion of prostaglandin E1 significantly increased cardiac output, but levosimendan increased cardiac output approximately twice as much as prostaglandin E1 (Fig. 1, Table 2). Although levosimendan infusion was stopped after 24 h the increase in cardiac output sustained after 48 h. The increase in cardiac output by prostaglandin E1 after 24 h was maintained at 48 h, as well. Furthermore, the double increase in cardiac output by levosimendan (+1.1±0.1 L/min) as compared to prostaglandin E1 (+0.6±0.1 L/min, p<0.001) after 24 h was also maintained at 48 h (Table 2).


Figure 1
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  		Fig. 1 Effect of levosimendan (boxes) and prostaglandin E1 (PGE1, filled circles) on cardiac output (A) and pulmonary capillary wedge pressure (B). Values represent absolute changes from baseline to 24 and 48 h and are expressed as mean±standard error of mean. *p<0.0001; **p<0.001.

 
Treatment with 24 h infusion of levosimendan and continuous prostaglandin E1 resulted in comparable decreases in pulmonary capillary wedge pressure (Fig. 1), pulmonary artery pressure, and systemic and pulmonary vascular resistance after 24 h with sustained effects after 48 h in both treatment groups. A small but significant increase in heart rate after 24 and after 48 h was noted in the levosimendan group, whereas no significant changes in heart rate were found in the prostaglandin E1 group. In both treatment groups mean peripheral artery blood pressure was significantly reduced to a comparable degree after 24 and 48 h (Table 2).

3.3. B-type natriuretic peptide
Baseline levels of B-type natriuretic peptide were 1190±162 pg/ml in the levosimendan group and 1143±160 pg/ml in the prostaglandin E1 group (not significant). Levosimendan decreased B-type natriuretic peptide by 328±83 pg/ml (–28%, p<0.001) to 861±129 after 24 h and by 257±96 pg/ml (–20%, p<0.05) to 933±123 pg/ml after 48 h. After 1 week B-type natriuretic peptide was 1077±152 pg/ml (not significant), which was not different from baseline levels. Prostaglandin E1 did not change B-type natriuretic peptide levels after 24 h (1055±152 pg/ml, not significant), but significantly reduced B-type natriuretic peptide by 172±71 pg/ml (–15%, p<0.05) to 971±137 pg/ml after 48 h and by 227±91 pg/ml (–20%, p<0.05) to 916±111 pg/ml after 1 week (Fig. 2).


Figure 2
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  		Fig. 2 Effect of levosimendan (boxes) and prostaglandin E1 (PGE1, filled circles) on B-type natriuretic peptide levels. Values represent absolute changes from baseline to 1, 2, and 7 d and are expressed as mean±standard error of mean. *p<0.05; **p<0.001.

 
3.4. Feasibility
Dosage had to be reduced in 12 patients (34%) due to hypotension during the 24 h levosimendan infusion but no patients needed a dose reduction during 48 h of prostaglandin E1 infusion (p<0.001). During the 24 h infusion, levosimendan had to be withdrawn in 3 patients, as follows: one patient had a fall in systolic blood pressure below 85 mmHg which did not recover within 30 min, one patient had a rise in serum creatinine over 2.5 mg/dl, and one patient experienced both of these side-effects. In one patient in the levosimendan group, serum creatinine rose over 2.5 mg/dl between 48 h and 1 week. In the prostaglandin E1-group there was one drug withdrawal due to diarrhoea after 48 h. No other side-effects requiring dose reduction or withdrawal occurred after 48 h.

In the three patients with a rise in serum creatinine over 2.5 mg/dl, the baseline values for systolic blood pressure were 96, 102, and 98 mmHg and the pulmonary capillary wedge pressure 25, 27, and 29 mmHg. After 48 h pulmonary capillary pressure was 25 mmHg in each of these three patients. Two of these patients received spironolactone.

There were no complications associated with the Hickman catheter.

3.5. Concomitant medication
With the exception of diuretics, concomitant medication was kept constant during the first 48 h. Between baseline and 1 week there was a slight but not significant reduction in furosemide dose in both treatment groups (levosimendan: 79±13 mg/d at baseline vs. 56±5 mg/d at 1 week, PGE1: 80±11 mg/d at baseline vs. 70±14 mg/d at 1 week). There was no change in angiotensin converting enzyme inhibitor or spironolactone doses. Between 48 h and 1 week, the dose of bisoprolol, which was the only beta-blocker used in these patients, was slightly increased (by 1 mg) in both groups, but no significant differences in beta-blocker dose were found between groups either at baseline or at 1 week follow-up.


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This study demonstrates that 24 h of levosimendan infusion leads to a greater hemodynamic improvement than continuous prostaglandin E1 infusion in patients with decompensated chronic heart failure. Furthermore, we have shown that continuous prostaglandin E1 induces a sustained decrease in B-type natriuretic peptide after 1 week, which did not occur with 24 h levosimendan infusion.

4.1. Hemodynamic differences between levosimendan and PgE1
Levosimendan increased cardiac output twice as much as prostaglandin E1, however, pulmonary capillary wedge pressure, pulmonary and systemic vascular resistance and pulmonary artery pressure were reduced to a similar degree by both drugs. There are two possible explanations for this finding. The first explanation is that levosimendan directly increases cardiac output by increasing myocardial contractility [30] whereas no such action has been described for prostaglandin E1. The second explanation is that we did not, as in previous studies, perform individual dose titration of prostaglandin E1, instead we used a predefined low dose of 2.5 ng/kg/min. Markedly higher increases in cardiac output can be reached with individual dose up-titration guided by hemodynamic response [31,32]. However, this approach is not feasible for routine clinical purposes and within a few weeks of chronic infusion most patients require significant dose reductions due to side-effects [20]. Therefore, for this study we decided to accept lower hemodynamic effects and used the fixed dose of 2.5 ng/kg/min prostaglandin E1.

4.2. Importance of hemodynamic changes as a therapeutic goal
Only decreases in pulmonary artery wedge pressure have been shown to correlate with survival [17], no such correlation has been found for cardiac output and other hemodynamic parameters. Therefore, we cannot expect a direct benefit on clinical outcome of the greater increase in cardiac output by levosimendan than by prostaglandin E1, especially since both drugs induced comparable decreases in pulmonary artery wedge pressure. Accordingly, levosimendan and prostaglandin E1 are probably comparable drugs as regards their short-term hemodynamic contribution to clinical outcome. However, the main therapeutic goal of intravenous therapy in decompensated heart failure is clinical stabilization to enable initiation or uptitration of oral neurohumoral heart failure therapy [33], especially beta-blockers, for which a higher cardiac output might be preferred. Since a greater increase in cardiac output can be gained by levosimendan compared to prostaglandin E1 without disadvantageous effects on myocardial energy metabolism [11] or interference with betablocker therapy [16], levosimendan might be the preferred drug in this clinical setting. However, currently there are no data available showing a correlation between drug-induced increases in cardiac output and clinical stabilization or successful initiation and uptitration of oral neurohumoral medication. Furthermore, the attempt to permanently increase cardiac output by inotropic drugs had deleterious effects on survival [34,35]. Therefore, the benefits of increases in cardiac output by levosimendan, should not be overestimated until more elucidating data exist.

4.3. Differential effects of levosimendan and prostaglandin E1 on B-type natriuretic peptide levels
Changes in B-type natriuretic peptide levels during treatment have been identified as strong predictors for mortality and early readmission in patients hospitalised for decompensated heart failure [25]. Therefore, the differential short-term behaviour of B-type natriuretic peptide during treatment with levosimendan and prostaglandin E1 in chronic decompensated heart failure might be crucial when comparing the drugs. Levosimendan decreased B-type natriuretic peptide by 28% after 24 h, and by 22% after 48 h but this effect had disappeared after 1 week. In contrast, continuous infusion of prostaglandin E1 did not reduce B-type natriuretic peptide until 48 h, but, more importantly, resulted in a significant, sustained 20% reduction of B-type natriuretic peptide after 1 week.

4.4. Importance of changes in B-type natriuretic peptide levels as a therapeutic goal
This raises the question of whether the initial extent and the time course of the decrease in B-type natriuretic peptide levels are important in decompensated chronic heart failure. With regard to the initial extent, short-term reductions in B-type natriuretic peptide by 26% after 1.4 days and 53% after 3.4 days have been reported with intravenous therapy designed to reduce filling pressures [36]. This marked decrease of B-type natriuretic peptide occurred more rapidly than the reduction in norepinephrine. Therefore, as the authors pointed out, a therapy that causes such a rapid decrease in B-type natriuretic peptide may lead to a period of hemodynamic instability with deficient endogenous vasodilation, while endogenous vasoconstrictor levels are still high. Furthermore, an excessive decrease in B-type natriuretic peptide might lead to a transient impairment of natriuresis and thus might be hazardous in patients with pre-existing kidney dysfunction. It is of interest to note that in the levosimendan group, in whom a rapid decrease in B-type natriuretic peptide occurred, we observed an elevation of serum creatinine in 8% of patients. In contrast, in the prostaglandin E1 group, in whom a slow but sustained decrease in B-type natriuretic peptide occurred, no elevation in serum creatinine was observed. Therefore, the benefit of rapid decreases in B-type natriuretic peptide levels is questionable, particularly if they are only transient as with levosimendan in our study.

With regard to the time course of the reduction in B-type natriuretic peptide levels, mid- and long-term reductions in B-type natriuretic peptide under conventional therapy have been previously reported and correlated with improved survival [37]. Consequently, it was suggested that therapy-induced decreases in B-type natriuretic peptide could be a treatment goal and B-type natriuretic peptide-tailored therapy might become a new approach in the treatment of heart failure [38]. Accordingly, our data demonstrating sustained (1 week) prostaglandin E1-induced decreases in B-type natriuretic peptide suggest that chronic prostaglandin E1 on top of optimized conventional therapy could beneficially influence clinical outcome in decompensated chronic heart failure. In contrast, the rebound in B-type natriuretic peptide levels back to baseline levels shortly after levosimendan infusion therapy may be associated with a markedly reduced benefit in terms of clinical outcome.

4.5. Short-term feasibility of levosimendan and prostaglandin E1
The relatively high rate of hypotension-related dose-reduction and drug-withdrawal and the significant increase in serum creatinine in three patients in the levosimendan group demonstrates the necessity of close blood pressure monitoring for dose-adjustments and repeated analyses of kidney function. In contrast, prostaglandin E1 did not create severe hypotension or other potentially fatal side-effects requiring intensive monitoring or dose adjustments and thus seems the more feasible therapy.

These side-effects of hypotension and increase in serum creatinine, must be seen in the context of volume management and concomitant medication. From our data it is very unlikely that these factors account for the differences in side effects between groups: The average pulmonary capillary wedge pressure was >24 mmHg in both groups and volume was substituted during infusion. Furthermore, after 48 h the pulmonary capillary wedge pressure was significantly but not drastically reduced to approximately 20 mmHg. In the 3 patients with an increase in serum creatinine, the minimum pulmonary capillary wedge pressure was 25 mmHg at baseline and after 48 h, indicating that hypovolemia was not the reason. Moreover, there was a trend to a reduction in furosemide dose in both groups. Finally, filling pressures and diuretics were not different between the treatment groups.

In contrast, the low rate of side-effects during prostaglandin E1-infusion might be dose related: The prostaglandin E1-dose of 2.5 ng/kg/min is only 12.5% of the previously reported target dose and 25% of the previously reported average dose at start of ambulatory therapy [20]. We cannot exclude, that at higher dosages prostaglandin E1 would have created the same rate of side effects as levosimendan. On the other hand, lower dosages of levosimendan might have produced less side effects. However, the lowest described therapeutic levosimendan doses are 0.1 and 0.05 µg/kg/min [15], which are the doses that we used in the present study, and it is not clear how much a further dose reduction would have reduced hemodynamic efficacy.

4.6. Limitations
We compared levosimendan at the lowest recommended doses [15] with prostaglandin E1 at a dose low enough to keep patients free of side-effects even during long-term infusion. Therefore, the conclusions drawn as regards side-effects are limited to the doses used in this study. Comparative dose efficacy studies are needed to evaluate dose-response relationships including lower levosimendan doses and higher prostaglandin E1 doses as regards hemodynamic efficacy, effects on natriuretic peptides, and side effects.

This was a prospective and randomized but open-label study. Blinding of the study treatment would have required central venous catheterization during the whole study for placebo administration in the levosimendan group with the risk of all associated complications including infection. Therefore, for ethical reasons, the study treatments were not blinded. However, BNP-values were determined in a blinded fashion.

4.7. Conclusion
A 24 h infusion of levosimendan leads to a greater increase in cardiac output than continuous prostaglandin E1. However, only continuous prostaglandin E1 infusion led to a sustained reduction in B-type natriuretic peptide for up to one week. Since changes in B-type natriuretic peptide levels during therapy are good prognostic markers in heart failure, whereas changes in cardiac output are not, there seems to be a more compelling rationale for the use of prostaglandin E1 in decompensated chronic heart failure rather than levosimendan. Furthermore, prostaglandin E1 infusion at 2.5 ng/kg/min seems the more feasible therapy as regards side-effects and the need for patient monitoring. How these potential advantages of prostaglandin E1 over levosimendan translate into improved clinical outcome requires further investigation.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
1 Consultant for Abbott Laboratories Austria. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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