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European Journal of Heart Failure 2008 10(12):1246-1254; doi:10.1016/j.ejheart.2008.09.006
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© 2008 European Society of Cardiology

Oral levosimendan in patients with severe chronic heart failure—The PERSIST study

Markku S. Nieminena,*, John G.F. Clelandb, Jaan Ehac, Yuri Belenkovd, Matti Kivikkoe, Pentti Põdere and Toni Sarapohjae

a Division of Cardiology, Helsinki University Central Hospital Helsinki, Finland
b Cardio-Vascular-Respiratory Division: Cardiology, The University of Hull United Kingdom
c Clinic of Cardiology, Tartu University Tartu, Estonia
d The A.L. Myasnikov Institute of Clinical Cardiology, Cardiology Research Center Moscow, Russia
e Cardiology Unit, Clinical Research and Development Orion Pharma, Espoo, Finland

* Corresponding author. Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland, Stenbäckinkatu 9, P.O. Box 100, 00290 Helsinki, Finland. Tel.: +358 9 4711; fax: +358 9 4715401. E-mail address: markku.nieminen{at}hus.fi (M.S. Nieminen).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Background: Intravenous levosimendan improves symptoms in acutely decompensated heart failure.

Aims: To evaluate the effects of oral levosimendan in severe chronic heart failure (CHF).

Methods: 307 patients with NYHA IIIB–IV CHF were randomly assigned, double-blind, to levosimendan 1 mg once or twice daily or placebo for at least 180 days. An exploratory primary end-point, the Patient Journey, a composite consisting of repeated symptom assessments, worsening heart failure and mortality during 60 days was used. Minnesota Living with Heart Failure quality of life score (MLHFQoL) and NT-proBNP were assessed repeatedly.

Results: Patients assigned to a lower dose of levosimendan had more severe CHF at baseline. No differences in symptoms emerged and worsening heart failure events and death were similar resulting in a similar Patient Journey score with levosimendan and placebo (p=0.567). Compared to placebo, a net improvement of 3–4 points in MLHFQoL at several time-points in favour of the combined levosimendan groups was observed (p<0.001) which was accompanied by a substantial and persistent reduction in NT-proBNP (–30–40%) (p<0.001).

Conclusion: Levosimendan improved QoL and decreased NT-proBNP but did not improve the Patient Journey composite in patients with severe CHF. Further research with this compound is warranted to clarify safety and efficacy.

Key Words: Levosimendan • Heart failure • Oral administration • NT-proBNP • Quality of life

Received March 10, 2008; Revised July 14, 2008; Accepted September 10, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Levosimendan is a calcium sensitizer and vasodilator. Given intravenously to patients with acutely decompensated heart failure, levosimendan, Simdax®, improves haemodynamics [1,2], neurohumoral disturbances and symptoms [3]. Despite earlier promising results [4,5], recent studies did not identify a mortality benefit compared to dobutamine [6] or placebo [3].

Few data on oral levosimendan exist. Single oral doses (1-4 mg) induced similar beneficial effects on pulmonary capillary wedge pressure and cardiac output to those seen with the intravenous formulation [7]. Oral levosimendan was also effective in weaning patients off intravenous inotropic agents in patients who were dependent on such drugs [8]. Levosimendan has an elimination half-life of 1 h, but its active metabolite (OR-1896) has a half-life of about 80 h [9] which accounts for the prolonged effect observed after infusion is stopped [10]. The effects of daily oral doses of 2-8 mg administered for 2 weeks were studied in 25 patients with NYHA III-IV chronic heart failure (CHF) [11]. A moderate positive inotropic effect was observed with 4-8 mg doses. Blood pressure remained unchanged with all doses. Mean heart rate was unchanged with doses up to 4 mg, but increased by about 8-10 bpm with 6-8 mg doses. The formation of the metabolite OR-1896 was linearly related to increasing levosimendan dose.

We present a pilot study of oral levosimendan for chronic treatment of severe CHF. Due to the lack of a widely accepted surrogate end-point, we developed an exploratory primary end-point to reflect the goals of treatment in this population, which are to relieve symptoms, reduce the number and length of hospitalisations and prolong life. The likelihood of achieving statistically significant results in any of these individual targets in a study with relatively small sample size is low and so we used a composite measure. Similar, but not identical, measures have been used previously [12-14].


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
The study protocol was approved by independent Ethics Committees and conforms with the principles outlined in the Declaration of Helsinki. All patients gave prior written consent. The study was designed, executed and overseen by the Sponsor and Steering Committee and an independent Data Monitoring Committee had access to unblinded Serious Adverse Event data.

2.1. Study population
Patients aged ≥18 years with severe symptoms of CHF of at least 3 months duration and treated with angiotensin converting enzyme inhibitors (ACEi) and beta-blockers, unless not tolerated, and additionally at least one of the following: diuretics, digitalis, aldosterone antagonist or angiotensin II receptor blocker (ARB), were enrolled at 32 centres in Finland, Estonia, Latvia, Lithuania and Russia. Patients had to have dyspnoea on minimal exertion or at rest (NYHA class IIIB-IV) both at screening and baseline and a left ventricular ejection fraction ≤30% (assessed within 12 months before screening). Patients also had to have either a hospitalisation or out-patient clinic visit in the previous 6 months for worsening heart failure (WHF) requiring intravenous treatment with diuretic, vasodilator or inotropic agents (patients in hospital but being prepared for discharge could be included) or to have a plasma concentration of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) ≥1000 pg/ml at screening.

The main exclusion criteria were severe ventricular outflow tract obstruction, cardiac surgery, coronary angioplasty or acute myocardial infarction within 30 days, scheduled heart surgery including transplantation in the next 6 months, systolic blood pressure <85 mmHg, heart rate ≥100 bpm, serum potassium <3.5 mmol/l and serum creatinine >450 µmol/l or on dialysis.

2.2. Study design
This was a randomised, double-blind, placebo-controlled, multicentre study with parallel groups. A screening visit took place 1-7 days before the initiation of study treatment. Patients were randomised to receive one of two doses of levosimendan (1 mg capsule once or twice daily, treatment groups LS-1 and LS-2, respectively) or corresponding placebo in addition to their existing treatment. The dose could be halved if symptomatic hypotension or a persistent increase in heart rate by ≥15 bpm unrelated to worsening heart failure (WHF) occurred or if the investigator judged that it was in the best interest of the patient. If further dose reductions were required, the study treatment was permanently stopped.

The minimum treatment period was 180 days. Visits were planned seven (±1), 30 (±5), 60 (±5), 90 (±10), 180 (±10) and 210 (±14) days after randomisation. Standardised assessment of symptoms was performed by weekly telephone contacts until day 60 and on days 120 (±10) and 150 (±10). After 180 days, patients were contacted by telephone every month (±10 days) and attended clinics every 3 months (±14 days) until the last patient completed 180 days of follow-up. At this time, the study treatment was stopped for all patients and an end-of-study visit was arranged 30 (+14) days thereafter.

2.3. End-points
An exploratory primary end-point, the Patient Journey, measured by repeated symptom assessments, WHF events and mortality during 60 days after randomisation was used. Symptoms were evaluated weekly by a 6-point symmetric scale of patient global assessment (PGA) which was converted to a numeric scale (between 0.0 and 1.0). The days between two visits/telephone contacts were scored as the average of the two assessments. WHF was defined as a hospitalisation with increased symptoms, and at least one of the following: 1) oral furosemide dose increased by at least 40 mg, 2) addition of a new class of oral diuretic or 3) administration of intravenous therapy (diuretic, vasodilator, inotropic). If the patient experienced WHF between two contacts, the PGA score was overruled and the score was –0.5 for those days. All days after death were counted as –1.0. Patient's individual Patient Journey score was defined as average score over the period of 60 days. Missing data was replaced using the last observation carried forward method.

Other efficacy end-points included time to death or WHF during the 180 days following randomisation, all-cause and cardiovascular mortality throughout the study treatment period, the number of days alive and out of hospital during the 180 days following randomisation, and changes in MLHFQoL assessments, plasma NT-proBNP concentrations, NYHA class and PGA.

Safety was followed by repeated heart rate and blood pressure measurements, adverse event inquiries, ECG assessments and laboratory variables.

2.4. Statistical analyses
Due to the limited experience with the primary end-point, no formal statistical power calculation was done. The sample size of 300 was selected to give a reasonable amount of safety data with each dose and to provide about 70% power for the secondary end-point ‘Time to death or WHF during 180 days’, assuming a 50% event rate in placebo treated patients and 30% effect size in favour of levosimendan ({alpha}=0.05).

Patients were randomly assigned to one of three groups in 1:1:1 allocation. Randomisation was balanced over study centre, country and the inclusion criterion: "recent hospitalisation or increased NT-proBNP value" using minimization and ‘biased-coin’ algorithm.

Comparisons were performed as all levosimendan vs. placebo. No formal testing of pair-wise comparisons was planned and therefore no adjustment for multiplicity was made. A nominal significance level of 0.05 was used.

Analyses included all randomised patients following the intention-to-treat principle. Baseline data was summarised with appropriate descriptive statistics. Patient Journey was compared across placebo and levosimendan groups using analysis of covariance (ANCOVA) with treatment (all levosimendan vs. placebo), recent hospitalisation/NT-proBNP randomisation strata and country as between factors and scored value of PGA at baseline as covariate. Time to death or worsening heart failure and mortality were analysed using a Cox-proportional-hazards model. Post-hoc analysis with commonly known baseline predictors of prognosis was performed using multivariate Cox-proportional-hazards model. In the final model, only significant predictors were chosen to adjust treatment effect. Change from baseline in MLHFQoL was analysed using repeated measures ANCOVA (RMANCOVA) model with the ‘time’ as within and the ‘treatment’ as between factors and baseline value as covariate. Treatment effect at each scheduled visit was also estimated using contrast statements using the above model. Similar analyses were conducted for vital signs, ECG conduction intervals and safety laboratory assessments. NT-proBNP plasma concentration was evaluated as median change from baseline to prescheduled time-points and analysed using the Kruskal-Wallis test. Number of days alive and out of hospital and NYHA were analysed with Cochran-Mantel-Haenszel (CMH) test, PGA with RMANCOVA and adverse events with Fisher's exact test.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Baseline characteristics
Patient enrolment was from March until August 2005. The disposition and baseline characteristics are presented in Fig. 1 and Table 1, respectively. About 90% of patients had been hospitalised for heart failure in the previous 6 months and only about 10% were recruited by the NT-proBNP criterion alone, most had ischaemic heart disease and were in NYHA class IIIB and about one third were in atrial fibrillation. More than 90% of patients were on diuretics, ACEi/ARB and beta-blockers and >70% were taking aldosterone antagonists. The overall study median [interquartile range (IQR)] NT-proBNP was 5118 (2538 to 10,617) pg/ml. The treatment groups were not perfectly matched. The lower levosimendan dose group had approximately 40% higher median NT-proBNP, had had more hospitalisations within the previous 12 months and received the highest diuretic dose, suggesting more severe disease at baseline compared to the other groups.


Figure 01
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  		Fig. 1 Disposition of study patients and primary reason for discontinuation.

 


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  		Table 1 Demographics and baseline characteristics

 
3.2. Primary end-point
Patient Journey scores were similar between the pooled LS and placebo groups for the 60 days after randomization (Table 2). The incidence of WHF events (six events in LS-1, two in LS-2, 11 in placebo) and mortality (six deaths in LS-1, two in LS-2, two in placebo) and PGA scores were similar.


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  		Table 2 Patient Journey during the 60 days after randomisation

 
3.3. Other efficacy end-points
The time to death or WHF, to all-cause and cardiovascular mortality and the number of days alive and out of hospital during 180 days after randomisation were similar in the pooled LS and placebo groups (Table 3).


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  		Table 3 Patient outcome during the 180 days after randomisation

 
During the entire study period (i.e. including exposure beyond 180 days), 15 (14.7%), eight (7.8%) and six (5.9%) patients died in LS-1, LS-2 and placebo groups, respectively. Most deaths were cardiovascular: 13 in LS-1, six in LS-2 and five on placebo. Sudden cardiac or arrhythmic death was reported in eight, two and five cases in LS-1, LS-2 and placebo groups, respectively, while death from WHF was reported in four patients in each LS group and none on placebo.

MLHFQoL score improved in patients assigned to placebo or levosimendan (Fig. 2). A net benefit of 3-4 points over placebo was seen in the pooled levosimendan groups (p<0.001), an effect that was distributed similarly across physical and emotional dimensions of the instrument. The NYHA class and PGA improved similarly in all groups.


Figure 02
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  		Fig. 2 Minnesota Living with Heart Failure quality of life score during the study (end of study refers to visit 30 days after stopping study drug).

 
The median NT-proBNP decreased rapidly in both LS groups and persisted until the end of treatment. The maximum median decrease was –1692 (IQR –3807 to –508) pg/ml in LS-1 group and –1777 (IQR –3638 to –423) pg/ml in LS-2 group; percent decreases were 33% and 41%, respectively. NT-proBNP was unchanged in the placebo group [0 (IQR –846 to 1777) pg/ml]. After treatment was stopped, NT-proBNP increased towards baseline values in both LS groups (Fig. 3). Patients with plasma NT-proBNP concentrations in the lowest quartile were least likely and those in the highest quartile most likely to die or have WHF (Fig. 4).


Figure 03
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  		Fig. 3 Median NT-proBNP during the study (end of study refers to visit 30 days after stopping study drug). Medians and IQR for each time point are shown in the accompanying table for clarity.
Median (IQR) pg/ml Baseline D7 D30 D60 D90 D180 End of study
6683 4568 4442 3849 4399 4145 5499
LS-1 (3553-12436) (2115-9814) (1904-8798) (2030-8375) (1946 -9137) (2030-7529) (2961-10,110)
4738 2961 2919 2538 3173 2961 3934
LS-2 (2453-9052) (1438-5076) (1438-5795) (1354-6091) (1481-6810) (1354-5922) (2030-7614)
4907 5753 4949 4484 4442 4907 4442
Placebo (1946-10,575) (2200-12,182) (2369-9941) (1777-9560) (1861-10,406) (2200-10,490) (2200-11,759)

 


Figure 04
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  		Fig. 4 Death or worsening heart failure by overall study quartile of NT-proBNP (pg/ml). Values in Q1 were 0 to 2538, Q2 2538 to 5118, Q3 5118 to 10617, and Q4 10617 to 97375. For placebo, LS-1 and LS-2 there were respectively 33, 17 and 27 patients in Q1 — 19, 28 and 30 in Q2 — 25, 23 and 30 in Q3 — and 25, 35 and 16 in Q4.

 
3.4. Predictors of death or WHF
The following baseline risk factors were included in a statistical model as predictors of death or WHF: age, sex, heart failure aetiology (ischaemic/other), ejection fraction, heart rate, systolic and diastolic blood pressure, QRS interval, haemoglobin, serum potassium, serum creatinine, NT-proBNP, use of a beta-blocker, ACEi/ARB, aldosterone antagonist, diabetes mellitus, atrial fibrillation, medical history of severe ventricular arrhythmias, implanted cardiac defibrillator, PGA, NYHA class and number of previous hospitalisations. Only NYHA class (IV vs. IIIB: hazard ratio 1.88), systolic blood pressure (above vs. below baseline median: hazard ratio 0.49), NT-proBNP (48% increase per incremental quartile) and previous hospitalisations (7.4% increase per hospitalisation) were statistically significant predictors of death or WHF. Treatment effects were adjusted for these four predictors in post-hoc analyses. The hazard ratio for LS-1 vs. placebo and LS-2 vs. placebo was 0.91 (95% CI 0.53 to 1.56) and 0.75 (95% CI 0.43 to 1.32), respectively. Unadjusted hazard ratios were 1.07 (0.63 to 1.80) and 0.81 (0.47 to 1.41), respectively.

3.5. Safety
Dose reductions occurred most often in LS-2 (18.4%), compared to 14.7% in LS-1 and 8.8% in placebo. In all groups, the most common reason for dose reduction was a persistent increase in heart rate. Permanent discontinuation of study treatment for reasons other than death was seen in 6.9%, 6.8% and 3.9% of the patients in LS-1, LS-2 and placebo groups, respectively (Fig. 1).

The most common adverse events are presented in Table 4. The most common adverse event was cardiac failure, which was reported numerically more often in the placebo group. Increased heart rate/palpitations were reported more frequently with levosimendan. Serious adverse events were reported with similar frequency in each group.


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  		Table 4 Adverse events reported by >5% of patients in at least one group

 
In both levosimendan groups, the median heart rate increased by seven (IQR –3 to 18) bpm by day 90 and by eight (0 to 18) bpm by day 180. In the placebo group, the median heart rate was similar at baseline and day 90, and by day 180 increased by one (–7 to 13) bpm (p<0.0001 compared to the pooled LS groups). The maximum decreases in the median systolic blood pressure were –2.0 (IQR –7.0 to 6.0) mmHg, –0.5 (–7.0 to 9.0) mmHg and –3.0 (–10.0 to 7.5) mmHg in LS-1, LS-2 and placebo groups, respectively (not significant).

Median creatinine clearance (using Cockroft-Gault formula) increased by 2.0 to 5.5 ml/min more in the pooled levosimendan groups compared to placebo (p<0.001). The median maximum increases were 4.6 ml/min (–1.2 to 13.0) (day 90), 6.8 ml/min (–0.9 to 15.0) (day 60) and 2.9 ml/min (–5.8 to 9.7) (day 90) in LS-1, LS-2 and placebo groups, respectively. The effect was evident within seven days of starting levosimendan.

The QT interval decreased more in the pooled LS groups than on placebo (p<0.0001). The median decrease on day 180 was 18 ms, 20 ms and 3 ms in LS-1, LS-2 and placebo groups, respectively and returned to baseline levels 30 days after withdrawal of treatment. This was heart rate related; QTC with Fridericia correction was virtually unchanged and similar in all three groups. New onset atrial fibrillation or flutter recorded on routinely taken ECGs occurred in 8.8%, 2.9% and 8.8% of the patients in LS-1, LS-2 and placebo groups, respectively. Ventricular tachycardia or fibrillation was reported in one, two and six patients in LS-1, LS-2 and placebo groups, respectively.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
This pilot study failed to show an effect of levosimendan compared to placebo on a novel primary end-point, the ‘Patient Journey’. Interpretation of the results was potentially confounded by baseline imbalance in the severity of heart failure. Improvements in quality of life score, renal function and reductions in NT-proBNP are encouraging but the modest persistent increase in heart rate is worrying and the failure to improve PGA or reduce the composite of death or worsening heart failure disappointing.

The patients had advanced heart failure. Most had been hospitalised for heart failure within the preceding 6 months and all had symptoms at rest or on minimal exertion. The mean MLHFQoL score of 57-60 at baseline is similar to the mean of 59 reported in the MIRACLE study evaluating the effects of cardiac resynchronization therapy in advanced heart failure [15] and higher than the mean of 51 reported in A-HEFT study investigating the effects of hydralazine/nitrate [14]. The median NT-proBNP of ~5100 pg/ml, which is more than double of that reported in the TEN-HMS and CARE-HF trials [16,17], further reflected the severity of disease. However, despite the relatively large number of patients, there were baseline imbalances between the groups indicating that patients assigned to the lower levosimendan dose had more severe heart failure. The most striking difference was in baseline NT-proBNP, which was approximately 40% higher in the lower levosimendan dose group. These patients also had more hospitalisations within 12 months before randomisation, were more often in NYHA class IV and were taking higher doses of diuretic. Baseline imbalances may have diminished the ability of the study to show differences between treatments. When treatment effect was adjusted, in a post-hoc analysis, for baseline predictors of worsening heart failure or death, trends to an improved outcome were observed with both doses of levosimendan. The point-estimate of the effect of the higher levosimendan dose suggested a 25% reduction in events, although with wide confidence intervals that could not exclude a 50% reduction or 30% excess. Studies of other inotropic agents have suggested worse outcomes with higher doses [18]. The trend for the higher levosimendan dose to be associated with a better outcome, if correct, suggests that the trend to poorer outcome with the lower dose may have occurred by chance.

The Patient Journey consisted of three components: repeated subjective symptom assessments, worsening heart failure events and all-cause mortality. None of the components was influenced significantly by levosimendan one way or the other. A possible explanation for the failure of the Patient Journey end-point was that it was insensitive to change. The majority of the score in short-term studies will depend on the tool used to measure symptoms or well-being. There was a substantial improvement from baseline in symptoms both by PGA and NYHA class in all three study groups, which was evident within 1 week from randomization. This improvement may be due to a placebo effect, a delayed effect of improved medical care instituted prior to enrolment (treatment changed little in the 7 days after enrolment) or ascertainment bias that is likely to occur when attempting to comply with study entry criteria. A placebo run-in period might have improved the ability of the PGA to detect differences between the groups. Assessment using MLHFQoL showed a difference in effect between levosimendan and placebo suggesting that it might be a more sensitive marker or that levosimendan is having effects on QoL not identified by PGA or NYHA class. The magnitude of improvement in MLHFQoL was similar to that reported for other pharmaceuticals recommended for the treatment of heart failure [14,19,20].

Although no significant difference in WHF events was observed, there were nearly 30% more events in the placebo group compared to the combined levosimendan groups. The concomitant decline in NT-proBNP suggests that this trend may not be a chance finding but a much larger study would be required to confirm or refute it. In studies of other interventions, such as ARBs [20], cardiac resynchronization therapy [17], as well as studies with intensified medical management [21,22], reduction in NT-proBNP has been a useful marker of an improved outcome [23].

There were numerically more deaths in patients assigned to low-dose levosimendan compared to the other groups. This was in keeping with their worse prognostic profile at baseline. The mortality in the control group in this study may have been spuriously low, reflecting the play of chance in a small study. Despite substantially higher NT-proBNP levels, suggesting markedly greater risk, the mortality at 6 months in the placebo group of PERSIST was 4%, compared to 7% and 6% in the control groups of the MIRACLE [15] and CARE-HF [17] trials, respectively. The lack of a relationship between dose of levosimendan and adverse outcome also suggests a chance finding. Studies of other inotropic agents have suggested worse outcomes with higher doses [24]. There was no clear pattern to the excess mortality and in particular no evidence of an increase in arrhythmias. Small studies may give confusing signals about the effect of a drug on outcome. For example, the RESOLVD study comparing candesartan, enalapril or their combination in 768 heart failure patients was prematurely terminated due to the greater number of deaths and hospitalizations in candesartan group [25]. However, a larger study showed a favourable effect of candesartan on morbidity and mortality [26].

Renal function is a powerful determinant of prognosis in heart failure [27,28] and improved more in levosimendan treated patients. Pre-clinical models suggest that levosimendan has renoprotective effects, possibly mediated by increases in cardiac output and renal vasodilatation [29,30]. Improved renal function should improve salt and water handling, increase excretion of waste products, improve diuretic responsiveness and reduce neuro-endocrine activation thereby reducing WHF [28].

An increase in heart rate similar to that observed with the intravenous preparation was observed [6,9,10]. The exact mechanism is unknown, but may be related to activation of baroreceptors [31]. In studies with intravenous levosimendan, a reduction in blood pressure is observed during infusion but the effect in the post-infusion period when only metabolites are present is modest [10]. No decrease in systolic or diastolic blood pressure was seen in the present study, consistent with the view that the main effect of the oral formulation is mediated through metabolites.

In conclusion, an experimental end-point, the Patient Journey, did not show differences between oral levosimendan and placebo in patients with severe CHF. However, MLHFQoL scores and renal function improved and NT-proBNP declined with levosimendan treatment. Further research on the safety and efficacy of oral levosimendan in patients with heart failure is warranted.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
We are grateful to Milton Packer, Prof (University of Texas, USA) for his input in the Steering Committee, to the Data Monitoring Committee; chair Karl Swedberg, Prof (University of Gothenburg, Sweden), John McMurray, Prof (University of Glasgow, UK) and Stuart Pocock, Prof (London School of Hygiene and Tropical Medicine, UK) to Thea Nieminen, RN and Niina Kaplas, RN (Orion Pharma, Espoo, Finland), and to Daira Laurenova, MD (ICON Clinical Research, Riga, Latvia).


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

  1. Nieminen M., Akkila J., Hasenfuss G., et al. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. JACC (2000) 36(6):1903–1912.[Abstract/Free Full Text]
  2. Slawsky M.T., Colucci W.S., Gottlieb S.S., et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation (2000) 102(18):2222–2227.[Abstract/Free Full Text]
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  6. Mebazaa A., Nieminen M.S., Packer M., et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure. The SURVIVE randomized trial. JAMA (2007) 297:1883–1891.[Abstract/Free Full Text]
  7. Harjola V.-P., Peuhkurinen K., Nieminen M.S., Niemelä M., Sundberg S. Oral levosimendan improves cardiac function and hemodynamics in patients with severe congestive heart failure. Am J Cardiol (1999) 83:4(I)–8(I).[Web of Science]
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  9. Kivikko M., Antila S., Eha J., Lehtonen L., Pentikäinen P. Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure. Int J Clin Pharmacol Ther (2002) 40(10):465–471.[Web of Science][Medline]
  10. 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(1):75–82.[Abstract/Free Full Text]
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