© 2006 European Society of Cardiology
Duration of the haemodynamic action of a 24-h infusion of levosimendan in patients with congestive heart failure
a Division of Cardiology, Helsinki University Central Hospital Haartmaninkatu 4, SF-00290 Helsinki, Finland
b Orion Pharma, Clinical Research Espoo, Finland
* Corresponding author. Tel.: +358 40 5245735; fax: +358 9 471 74574. mika.laine{at}hus.fi
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Abstract |
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 TopNotes Abstract 1. Methods2. Results3. DiscussionReferences |
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Aims: To determine the duration of haemodynamic and neurohormonal action of a 24-h infusion of levosimendan in heart failure.
Methods and results: This was a double-blind, parallel group study in patients with New York Heart Association class II to IV heart failure. Twenty-two patients, with left ventricular ejection fraction <35% and pulmonary capillary wedge pressure (PCWP) above 12 mmHg, were randomised to receive either levosimendan (12 µg/kg followed by a continuous infusion of 0.1–0.2 µg/min) or placebo. Invasively measured cardiac output (CO) increased from 4.3 l/min to 5.4 l/min in the levosimendan group at 6 h. PCWP decreased from 20 mmHg to 15 mmHg in response to levosimendan. Echocardiographically measured maximal effect on PCWP occurred after 6 h, whereas CO reached its highest value at 24 h. The estimated duration of the decrease in PCWP was 7–9 days, and in CO was 12–13 days. Plasma NT-proANP and NT-proBNP levels reached their lowest values at days 3 and 2, and the treatment effect was estimated to last 16 and 12 days, respectively. The long-acting haemodynamic responses reflect levels of the active metabolites OR-1896 and OR-1855, maximal metabolite levels occurred at day 3.
Conclusions: Levosimendan infusion achieved a rapid improvement in haemodynamic parameters in patients with congestive heart failure with maximal effects occurring 1–3 days after starting the infusion, effects were sustained for up to at least a week.
Key Words: Calcium sensitizer • Heart failure • Vasodilators • Inotropic agents
Received June 17, 2005; Revised February 27, 2006; Accepted April 24, 2006
Levosimendan is a new calcium-sensitizing and vasodilatory agent developed for the short-term treatment of decompensated chronic heart failure. Levosimendan increases myocardial contractility [1], reduces filling pressure [2] and dilates both the peripheral and coronary blood vessels [3,4]. The positive inotropic action of levosimendan is due to the calcium-dependent binding of the drug to cardiac troponin C [5,6], whilst it's vasodilative effect is mainly due to the opening of ATP-dependent K-channels in vascular smooth muscle [7,6].
Levosimendan is used in clinical practice for the treatment of acutely decompensated, severe heart failure. To date, clinical studies have demonstrated the efficacy and good tolerability of levosimendan in over 1000 adult patients with decompensated heart failure of both ischaemic and non-ischaemic origin [8,9]. In contrast to earlier inotropic agents, levosimendan does not seem to increase mortality in acute heart failure [8,9]. It is presumed that both levosimendan and its active metabolite, OR-1896, are involved in the cardiovascular effects. However, the exact duration of the haemodynamic effect of a single levosimendan infusion is unclear. There are also no data to indicate how frequently levosimendan may be administered.
Due to an active long acting metabolite [10], the haemodynamic effects of a levosimendan infusion seem to continue for several days after stopping the infusion. However, the effects of levosimendan on left ventricular filling pressure and CO have not been evaluated beyond 48 h from the start of the levosimendan infusion. This is mainly due to the fact that invasive catheters cannot be used for longer than 2-3 days. To overcome this problem, we used previously described Doppler echocardiography methods to estimate PCWP and CO levels non-invasively, for up to 14 days [11-13].
The aim of this study was therefore to evaluate the duration of action of a 24-h levosimendan infusion. The primary efficacy variable was the duration of the decrease in PCWP. Secondary variables included the duration of the increase in CO, the maximum change from baseline in PCWP and CO. In addition, NT-proANP and NP-proBNP levels were measured to evaluate the duration of neurohormonal response to levosimendan treatment.
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1. Methods |
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TopNotesAbstract1. Methods2. Results3. DiscussionReferences |
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1.1. Study population
Twenty-two patients, (11 levosimendan, 11 placebo) were enrolled in the study. We included patients over 18 years of age with chronic congestive NYHA II-IV heart failure, left ventricular ejection fraction below 35%, and pulmonary wedge pressure >12 mmHg estimated by the Pozzoli method (described below in detail). Patients had to be clinically stable with no changes in their medication for at least 1 week before inclusion in the study. We did not include women of childbearing potential, or any patient with severe obstruction of ventricular outflow tracts, atrial fibrillation, more than mild-to-moderate mitral aortic regurgitation or second degree (Mobitz type II) block or third degree heart block. Patients treated with amrinone, milrinone, dobutamine, dopamine, intravenous diuretics or intravenous nitrates within 2 weeks prior to randomisation or with a history of Torsades de Pointes ventricular tachycardia were also excluded.
1.2. Study design
This was a phase II, randomised, double-blind, placebo-controlled, parallel group, single centre study in patients with stable symptomatic congestive heart failure. The study consisted of three periods: (i) a screening visit performed within 2 weeks of the start of the study drug infusion, (ii) 24-h infusion treatment period and (iii) a follow-up period which continued for 2 weeks after completion of the treatment period. Based on the measurements obtained during the screening visit, patients with a satisfactory echo-window, left ventricular ejection fraction <35% and PCWP above 12 mmHg were included in the study.
1.3. Haemodynamic measurements and study drug infusion
A Swan-Ganz catheter was inserted through the right jugular vein into the pulmonary artery followed by a stabilisation period of 2.5 h. Baseline assessments of PCWP, PAP, CO, BP, HR and echocardiographic variables were performed twice within 30 min before starting the study drug infusion. Parallel invasive and echocardiographic measurements were performed at baseline and then 30 min, 2 h and 6 h after the start of the levosimendan or placebo infusion. Blood pressure was measured using a standard arm cuff monitor, and heart rate was determined from EKG.
Patients were randomised in 1:1 ratio to receive either levosimendan or placebo. Study drug administration was initiated with a loading dose of 12 µg/kg of levosimendan or placebo delivered over 10 min. This was followed by a continuous infusion of 0.1 µg/kg/min for 50 min. If the dose was well tolerated the infusion rate was increased to 0.2 µg/kg/min for a further 23 h. After the study drug was started, the haemodynamic assessments were repeated at 30 min, and at 2 and 6 h, the Swan-Ganz catheter was then removed. The non-invasive haemodynamic assessments were repeated at 24 h.
The study drug infusion was stopped 24 h after it was first started unless it had been discontinued earlier due to a dose-limiting event. Dose limiting events were defined as: a decrease in systolic blood pressure to 85 mmHg or less or symptomatic hypotension, an increase in heart rate to 120 bpm or more for over 10 min, angina pectoris or new electrocardiographic evidence of myocardial ischaemia, or new tachyarrhythmia such as ventricular tachycardia.
Follow-up visits took place 2, 3, 5, 7, 9 and 14 days after the beginning of the study. On these visits echocardiographic measurements were performed and blood pressure and heart rate were measured after half an hours rest in the supine position.
1.4. Ultrasound measurements
An Acuson Sequoia ultrasound system with 2.5-3.75 MHz probes was used for the Doppler echocardiographic measurements. Blood flow velocity curves were recorded at a sweep speed of 100 mm/s. Left ventricular ejection fraction was assessed by two-dimensional apical two- and four-chamber views using the modified Simpson rule. Mitral and pulmonary flow measurements were performed as described earlier [11].
One investigator performed all of the echocardiographic recordings. All echocardiographic data were stored in digital form on magneto-optic discs. Recordings were analyzed later in random order by another investigator who was blinded to the results of invasive measurements and treatment. All data were averaged over 5 consecutive technically acceptable cardiac cycles.
Estimation of the PCWP was calculated as reported earlier [11]. Cardiac output was calculated as the product of heart rate, time-velocity integral and the cross-sectional area of the LVOT [12].
1.5. NT-proANP, NT-proBNP and metabolite measurements
Blood samples (4 ml) for natriuretic peptide measurements and for determination of levosimendan and its metabolites OR-1855 and OR 1896, were taken into pre-cooled EDTA tubes. Samples were taken at baseline (0-sample) and on the first study day 30 min, 2 h, 6 h and 24 h after the start of the infusion and in the mornings of days 2, 3, 5, 7, 9 and 14 after the start of the study drug infusion. During the infusion, blood samples were drawn from the opposite arm levosimendan was infused.
Concentrations of levosimendan and its metabolites OR-1855 and OR-1896 in plasma were determined by liquid chromatography tandem mass spectrometry (Orion Pharma, Helsinki, Finland). Natriuretic peptide plasma concentrations were determined as described earlier [14].
1.6. Statistical analysis
Demographic, baseline characteristics and vital signs were summarised by treatment group using mean, standard error, medians and percentages, as appropriate. Duration of the treatment effect in echo PCWP, echo CO, NT-proBNP and NT-proANP was calculated using linear random coefficient model with effect for treatment, visit and treatment-visit interaction. In the treatment group, time point of maximum change from baseline and the time points thereafter were used to analyze the duration of the haemodynamic effect. In placebo subjects, all time points were used in the linear model. In addition, area under the curve (AUC) analysis was used to calculate the treatment effect in CO and PCWP.
Correlation between echocardiographically and invasively measured PCWP and CO was calculated using Pearson correlation coefficient. Also analysis of covariance (ANCOVA) was used in evaluating agreement of measurement methods. The ANCOVA model included effect for visit, subject and method of assessment. Repeatability of echo measurement method was examined using within patient coefficient of variation. Also the mean difference between the echocardiographically and invasively measured parameters during the 6 h was calculated. The change from baseline in the invasively measured parameters was analysed using repeated measures ANOVA model with effects for treatment, visit and treatment-visit interaction.
The effect of levosimendan on NT-proBNP and NT-proANP was evaluated using percentage change from baseline. The difference between treatment groups was analysed using non-parametric Kruskal-Wallis ANOVA.
1.7. Ethical considerations
The study protocol was approved by the Ethics Committee of the Helsinki University Central Hospital and conducted in accordance to the Declaration of Helsinki. All patients gave written informed consent before entering the study.
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2. Results |
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TopNotesAbstract1. Methods2. Results3. DiscussionReferences |
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2.1. Demographics
28 patients were screened and 22 were included in the study according to the predetermined criteria. The major demographic parameters are shown in Table 1. The mean age of the subjects was 55 (range 41-72) years. The majority of the subjects were male (82%), all four females were in the placebo group (46%). The medical history of the subjects included myocardial infarction in 46% of patients in the levosimendan group and 18% in the placebo group.
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2.2. Haemodynamic effects during the first 6 h
Invasively measured PCWP decreased rapidly in response to the levosimendan treatment (Table 2). After 30 min PCWP had decreased 3.6±4.9 mmHg in comparison with no change from baseline in the placebo group. The decrease in PCWP levels continued in the levosimendan group and the difference as compared to baseline after 6 h was –5 mmHg (p<0.01). Similarly, right side pressures (PAP and RAP) decreased effectively in response to levosimendan infusion, whereas an increase in PAP and RAP was observed in the patients receiving placebo.
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Levosimendan treatment increased CO 1.3-fold from baseline (Table 2). The increase in CO by levosimendan treatment was statistically significant (p<0.01) at all time points (30 min, 2 h, and 6 h) as compared to placebo. Left ventricular stroke volume (SV) increased from 69 to 84 ml in the levosimendan group in contrast to the placebo group where a slight decrease in SV was detected.
2.3. Dose limiting effects
The study drug infusion was well-tolerated with no permanent discontinuation of the 24-h infusion. There were 3 dose limiting events during the study, all occurring in patients receiving levosimendan. In one case levosimendan was temporarily discontinued due to low systolic blood pressure (81/41 mmHg). The hypotensive episode lasted for 1 h 19 min. Study drug infusion was restarted at half of the original infusion rate when blood pressure had increased up to 92/46 mmHg. In two cases the levosimendan dose was reduced by 50% due to the physician judging that it was in the best interest of the patient to reduce the dose due to low pulmonary capillary wedge pressure.
2.4. Correlation between echocardiographically and invasively measured PCWP and CO
Echocardiographically measured PCWP and CO had a good correlation with invasively measured PCWP and CO at baseline. The Pearson correlation coefficients at baseline were 0.63 and 0.64, respectively. Echocardiographically measured changes in PCWP and CO correlated well with the alterations in the invasively measured parameters. In co-variance analysis the correlation coefficients between invasively and echocardiographically measured PWCP and CO were 0.82 (p<0.001) and 0.80 (p<0.001), respectively.
The difference between the echocardiographically and invasively measured absolute PCWP using the Bland-Altman method was –1.7 mmHg, 0 95% CI –2.9 to –0.6. The difference between the echocardiographically and invasively measured change in PCWP by Bland-Altman analysis was –0.1 mmHg, 95% CI –1.6 to 1.4. Reproducibility of echocardiographically measured PCWP was calculated from the two baseline measurements (–20 min and –10 min). The mean difference between the measurements was 0.54 mmHg (95% CI –1.49 to 2.57 mmHg).
2.5. Haemodynamic and neurohormonal effects up to 14 days
The mean heart rate at baseline was 66±10 bpm in the placebo group and 63±9 bpm in the levosimendan group. During levosimendan infusion, heart rate increased from baseline by up to 7±10 bpm at 5 h and continued to increase until day 3 by up to 12±9 bpm. Heart rate remained elevated up to day 9 after the start of the levosimendan infusion. In the placebo group heart rate fluctuated by up to 4±11 bpm.
The mean systolic blood pressure at baseline was 125±17 mmHg in the placebo group and 116±11 mmHg in the levosimendan group. There was a decrease from baseline systolic blood pressure in the levosimendan group during the first 24 h, the maximum decrease of 5 mmHg occurring at 8 h (Fig. 1). Diastolic blood pressure at baseline was 74±9 mmHg in the placebo and 71±8 mmHg in the levosimendan group. The changes from baseline in diastolic blood pressure were small in both study groups. In the levosimendan group there was a small, but consistent decrease in diastolic blood pressure during the 24-h study drug infusion, which continued until day 3.
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The duration of the haemodynamic action of levosimendan was determined by serial echo measurements on days 2, 3, 5, 7, 9 and 14 after the start of the study drug infusion (Fig. 2). When calculated from the treatment induced decrease in PCWP levels, the duration of a 24-h levosimendan treatment was 9 days as determined by the linear model (Fig. 2A). Using the same methods an increase in CO was estimated to last 13 days (Fig. 2B). By AUC analysis maximal drug effect on PCWP was detected at 6 h (Fig. 3) whereas the effect on CO peaked at the end of 24-h levosimendan infusion (Fig. 3). By AUC analysis the duration of the treatment effect was 7 days for PCWP and 12 days for CO.
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Mean baseline values for NT-proANP were 900±558, and 1622±1072 pmol/l in the placebo and levosimendan groups. NT-proBNP levels were 633±556 and 1008±1048 pmol/l, respectively. The differences at baseline in NT-proANP and NT-proBNP levels were not statistically significant, p=0.249 and 0.510 respectively. Both NT-proANP and NT-proBNP levels decreased significantly in response to levosimendan treatment (Fig. 4). However, the decrease in NT-proBNP level in response to levosimendan infusion was detected later than the response in NT-proANP levels, a statistically significant difference occurring at 24 h after the start of the infusion (median change –50% vs –19%, p=0.003). A statistically significant decrease in NT-proANP levels was observed 2 h after initiation of the study drug (median change –41% vs –12%, p=0.029). NT-proANP reached its lowest value at day 3 and NT-proBNP at day 2. By using the linear model, estimated duration of the neurohormonal effect was 16 days for NT-proANP and 12 days for NT-proBNP.
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2.6. Metabolites OR-1855 and OR-1896
Levosimendan was rapidly eliminated after discontinuation of the infusion (Fig. 5). The metabolites of levosimendan were formed and eliminated slowly, with half-lives (78-89 h) considerably longer than those of the parent compound (Fig. 5). Peak concentrations of OR-1855 and OR-1896 were achieved 2-4 days after starting the infusion of levosimendan.
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2.7. Adverse events and safety laboratory values
A total of 25 adverse events were reported in 12 patients during the study. There were more adverse events in patients receiving placebo (7/64%) than levosimendan (5/46%). Adverse drug related events were reported in an equal number of patients receiving placebo (n=3) and levosimendan (n=3). One patient in the levosimendan group had a headache. There were two cardiac disorders, palpitations and atrial fibrillation, reported in the levosimendan group. Both were reported after the study drug infusion.
Adverse events reported were considered mild except one report of severe abdominal pain, also reported as a serious adverse event. The aetiology of the abdominal pain was judged to be due diverticulitis of the colon. Laboratory assessments revealed a CRP elevation up to 177 mg/l (normal <10 mg/l). The subject was treated with i.v. and oral antibiotics and was hospitalised for 6 days. The causal relationship of the study treatment was assessed as unlikely. This patient was included in the analysis with the exception of the two last visits, when he was being treated for diverticulitis.
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3. Discussion |
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TopNotesAbstract1. Methods2. Results3. DiscussionReferences |
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The present study shows that the haemodynamic effects of levosimendan treatment continue for several days after stopping a 24-h infusion. The primary end-point of the study, the estimated duration of change in PCWP, was 7-9 days. The duration of the increase in CO was slightly longer lasting 12-13 days.
The pharmacokinetics of levosimendan are linear and the plasma concentrations of the drug increase in a dose-proportional manner following single dose IV administration and intravenous infusion of the drug [1,2,15]. Levosimendan is rapidly distributed to the tissues and 97-98% of the drug is bound to plasma proteins, mainly human plasma albumin. The drug has a half-life (t
) of approximately 1 h and steady state concentrations are achieved within 4 h without a bolus [16]. Levosimendan is reduced in the gut to an amine metabolite OR-1855, which is further acetylated to OR-1896. OR-1896 has a similar pharmacological profile to the parent compound but has a t of 70-80 h [16,17]. Following the cessation of a 24-h infusion of levosimendan, peak concentrations of OR-1896 are reached at 1-4 days (mean 2 days) and invasively measured haemodynamic effects continue at least 24 h after cessation of the drug infusion [18].
Data from non-invasive studies, following heart rate and blood pressure, suggest that the maximal haemodynamic response to levosimendan occurs 1-2 days after stopping the infusion [10,17]. In accordance with these results, in the present study mean CO level increased up to 24 h and remained relatively stable until day 3. The maximal effect on PCWP was detected earlier than the effect on CO, suggesting that the vasodilatory effect of levosimendan is seen earlier than the increase in myocardial contractility. This pharmacodynamic difference may be explained by the intracellular target of the calcium sensitizer action, whereas levosimendan-induced vasodilatation is mediated mainly by ATP-dependent K-channels on plasma membrane [6,7].
The haemodynamic responses after the end of the infusion period followed the levels of the active metabolites OR-1896 and OR-1855, the maximal metabolite levels occurring at day 3. Although the absolute concentrations of the metabolites are lower as compared to the parent drug, the free concentrations of the metabolites compare to the unbound levels of levosimendan. The free plasma fraction of levosimendan is 
3%, whereas the free plasma fractions of the metabolites are 58% for OR 1855 and 61% for OR 1896 [16]. The duration of the haemodynamic response was evaluated by serial non-invasive estimates of PCWP and CO by echo. Non-invasive measurements had a fair correlation to invasively measured values but seemed to underestimate the absolute changes in PCWP and CO. Although the underestimation may also shorten the estimated duration of the effect of levosimendan, it is unlikely to have a major effect on the results. Both linear analysis and analyses of areas under the curve suggested that the treatment effect on PCWP was sustained for about a week. The effect on CO was estimated to last slightly longer. The profile of the haemodynamic effects over time paralleled the corresponding plasma profiles of the active metabolites of levosimendan.
Another way to estimate the duration of the haemodynamic action of levosimendan is to measure neurohormonal responses to the treatment. Natriuretic peptides ANP, BNP, and the N-terminal parts of the pro-peptides are released from the atria and ventricles in response to myocardial stretch [19]. Natriuretic peptide levels reflect myocardial diastolic pressure load [19,20] and they can be used in monitoring the treatment of patients with congestive heart failure [21]. Accordingly, plasma NT-proANP and NT-proBNP levels decreased rapidly in response to levosimendan infusion. Mean NT-proANP levels reached their lowest value at day 3 and NT-proBNP at day 2. The effect on the peptide levels was estimated to last 16 and 12 days respectively. These results are in-line with the haemodynamic estimations and plasma metabolite levels. Further studies are needed to determine whether natriuretic peptides can be used as surrogate markers to guide the re-administration of levosimendan to achieve optimal clinical benefit with minimal risks.
The formation of the active metabolite and consequent prolonged haemodynamic action of levosimendan has certain benefits in the treatment of patients with severe heart failure. Stopping the infusion at 24-h does not lead to abrupt changes in haemodynamics and the long duration of action gives patients time to recover and allows them to be weaned from intravenous lines. As compared to short acting inotropes, levosimendan treatment might be ideal for intermitted inotropic therapy. After a single 24-h infusion in the LIDO study, the days alive and out-of-hospital were statistically significantly higher in the levosimendan than in the dobutamine group during the 180 days follow-up [8].
The long duration of action may also have disadvantages. In a case of an unnecessary profound vasodilatory effect, administration of intravenous fluids or vasoconstrictive drugs, such as noradrenaline, might be temporarily needed. However, the lowest systolic and diastolic blood pressures were observed as early as 4-8 h after starting the infusion in the present study. During this time, the formation of the active metabolite is minor, and the haemodynamic effects can be rapidly reversed by stopping levosimendan infusion. In our study, levosimendan infusion was discontinued in one case due to low systolic blood pressure. Blood pressure returned to the pre-treatment levels within an hour after stopping the infusion and the treatment was resumed with no further problems.
3.1. Limitations of the study
Due to the relatively small number of patients, there were some differences between the randomised study groups. The baseline NT-ANP and NT-BNP levels were higher in the levosimendan group as compared to the placebo group suggesting that levosimendan treated patients had more severe heart failure. This is also supported by the higher PCWP (20 vs 17 mmHg) and lower CO (4.3 l/min vs 5.0 l/min) values in the levosimendan group in comparison with the placebo group. In addition, echocardiographic methods seemed to underestimate the treatment-induced changes in PCWP and CO. However, these limitations are unlikely to affect the estimations about the duration of the treatment effect.
In summary, we showed that the treatment effect of levosimendan continued for several days after a 24-h infusion in heart failure patients. A clear response to levosimendan in both NT-proANP and NT-proBNP levels, closely coinciding with the sustained haemodynamic response, was demonstrated. The maximal haemodynamic and neurohormonal effect of a 24-h levosimendan infusion occurred within 1-3 days after starting the infusion. The haemodynamic effect seemed to be sustained for up to at least 1 week. The long lasting haemodynamic effects after a single infusion are most probably due to the formation of active metabolites of levosimendan.
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TopNotesAbstract1. Methods2. Results3. DiscussionReferences |
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The study was supported by a grant of Orion Pharma Pharmaceuticals, Espoo, Finland. 
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