| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
BRIEF REPORT/CLINICAL STUDIES |
From the ukb, Academic Teaching Hospital, Charité Medical School, Berlin, Germany (Dr Kleber, Dr Sonntag); Christian-Albrechts-Universität, Klinik für Herz- und Gefäßchirurgie, Kiel, Germany (Dr Costard-Jäckle); Universitätsklinikum Heidelberg, Abteilung Innere Medizin III, Heidelberg, Germany (Dr Borst); Akademiska hospital, OTM division, Kardiologi, Uppsala, Sweden (Dr Wikström); Ernst-Moritz-Arndt-Universität, Zentrum für Innere Medizin, Greifswald, Germany (Dr Bollmann, Dr Ewert); and Orion Corporation, Orion Pharma, Espoo, Finland (Dr Petterson, Dr Pohjanjousi, Dr Kivikko).
Address for reprints: Franz X. Kleber, MD, FESC, ukb, Academic Teaching Hospital, Charité Medical School, Warener Str 7, 12683 Berlin, Germany.
Key Words: Pulmonary hypertension • right heart failure • potassium channel opener • calcium sensitizer
Pulmonary hypertension is a rare disease (30 to 50 cases per million in the general population),1 characterized by an increase in pulmonary vascular resistance (PVR), which often results in right ventricular failure and death. Various therapeutic approaches have been developed,2-7 but the treatment of patients with overt heart failure still remains a challenge.
Levosimendan is a myocardial calcium sensitizer8-12 and vasodilator.13-15 The intravenous formulation of levosimendan has been studied in several randomized comparative studies in patients with decompensated heart failure, and it has produced significant, dose-dependent increases in cardiac output (CO) and stroke volume and decreases in pulmonary capillary wedge pressure (PCWP) and pulmonary artery pressure.16-19 Preliminary data indicate similar beneficial hemodynamic effects in patients with pulmonary hypertension, including a reduction in PVR and transpulmonary gradient (TPG) in 6 patients with end-stage heart failure and severe pulmonary hypertension.20
Levosimendan itself disappears rapidly from the circulation after intravenous infusion, with an elimination half-life of about 1 hour,21 but its active metabolite OR-1896 has a considerably longer elimination half-life (
80 hours) and is likely to exert effects for several days.22,23
The aim of the present study was to evaluate the acute and long-term hemodynamic effects of repetitive intravenous infusions of levosimendan in patients with various forms of pulmonary hypertension.
METHODS
Study Design
This randomized, placebo-controlled, double-blind, parallel-group study was conducted in 4 centers in Germany and 1 center in Sweden. The study protocol and amendments were approved by the institutional ethics committees of all participating centers, and all patients provided written informed consent. To obtain more data with the study drug, a 2:1 allocation for levosimendan and placebo, respectively, was used. The sample size calculation was based on a previous levosimendan study.17 To achieve a placebo-adjusted improvement in PVR of 29% (SD, 22%) with a 0.050 2-sided significance level and 80% power, 16 levosimendan and 8 placebo patients were needed.
Patients
The main inclusion criteria were composed of the following:
4 mm Hg, and edema or jugular venous distension within the past 6 months; 20% by invasive testing of vasodilator reactivity; and 30 mm Hg at baseline. Concomitant medications for pulmonary hypertension were required to be stable for at least 2 weeks prior to study enrollment.
Patients were excluded from the study if they had aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy, planned lung transplantation within 3 months after study enrollment, severe hypoxia (pO2 <60 mm Hg), significant hypotension (systolic blood pressure 
90 mm Hg), heart rate 125 bpm persistent for at least 5 minutes, or serum potassium <3.5 mmol/L or >5.4 mmol/L at screening. Additional exclusion criteria were use of positive inotropic agents (with the exception of digoxin) within 2 days prior to study enrollment, acute coronary syndrome within 4 weeks, severe hepatic impairment, significant renal insufficiency, a history of torsades de pointes, pregnancy, and breastfeeding.
Randomization
Eligible patients were randomized to receive either levosimendan (Orion Corporation, Espoo, Finland) or placebo in a 2:1 ratio in addition to standard therapy for pulmonary hypertension. Randomization was by means of a computer-generated code, with treatment codes stored at the Department of Biostatistics and Data Management of Orion Pharma (Espoo, Finland). The total follow-up time after randomization was 12 weeks.
Study Drug Administration
After the baseline hemodynamic measurements, the study drug was initiated with a loading dose of 12 µg/kg infused over 10 minutes, followed by a continuous infusion of 0.1 µg/kg/min for 50 minutes. If this initial dose was well tolerated, the rate of infusion was increased to 0.2 µg/kg/min and maintained for 23 hours. Dose reduction to 0.1 µg/kg/min was allowed in the event of hypotension or tachycardia. The regimen followed the posology in systolic heart failure patients.
The study drug was then readministered 4 times at 2-week intervals as a continuous infusion of 0.2 µg/kg/min for 6 hours.
Invasive Hemodynamic Measurements (Right Heart Catheterization)
A triple-lumen thermodilution Swan-Ganz catheter was inserted into a central vein under local anesthesia for the measurement of PCWP, systolic pulmonary artery pressure, mRAP, and mixed venous oxygen saturation. Recordings were performed at the end of expiration with the patient breath holding during at least 5 consecutive cardiac cycles. CO was calculated according to Fick, using tabulated oxygen uptake, or by thermodilution technique. PVR and TPG were calculated according to standard formulae.
The first invasive hemodynamic measurements were performed at baseline and at 1, 2, 4, 6, 8, and 24 hours after starting the 24-hour study drug infusion. The second invasive assessments at 8 weeks were performed at 1, 2, 4, and 6 hours after starting the 6-hour study drug infusion.
Patient Classification
During the course of the study, the etiology of pulmonary hypertension was classified as primary or secondary; the secondary cause was then further specified. The current Venice classification24 came into use after the initiation of this study; therefore, the patients were reclassified to match the new classification. As examples, primary hypertension in our original classification is according to Venice nomenclature, pulmonary arterial hypertension (idiopathic) and secondary pulmonary hypertension due to portal hypertension is now pulmonary arterial hypertension (portal hypertension).
Endpoints
Efficacy. The primary objective was to compare the intergroup change in PVR at the end of the initial 24-hour infusion.
The secondary objectives were to evaluate the longer-term (8 weeks) effects of levosimendan on PVR and acute and longer-term effects of levosimendan on other hemodynamic variables.
Safety. Safety of the study drug was evaluated by repeated measurements of blood pressure and heart rate and by assessment of adverse events.
Plasma levels of levosimendan and its metabolites. Blood samples of 4 mL were drawn before and at 6, 24, 48, and 96 hours after starting the 24-hour study drug infusion. Repeat sampling was performed before and 6 hours after the infusion of study drug at 2, 4, 6, and 8 weeks. The plasma concentrations of levosimendan and its metabolites OR-1855 and OR-1896 were determined by liquid chromatography tandem mass spectrometry at the Department of Bioanalytics and Pharmacokinetics, Orion Corporation (Espoo, Finland). Details of the analytic method have been published.25 The lower limit of quantitation was 0.200 ng/mL for levosimendan and 0.500 ng/mL for the metabolites OR-1855 and OR-1896, respectively. Owing to the limited number of blood-sampling time points, no pharmacokinetic variables were calculated.
Vital signs. Heart rate and blood pressure were measured at baseline and at 1, 2, 4, 6, 8, 24, and 48 hours after starting the 24-hour study drug infusion and 1, 2, 4, and 6 hours after starting the 6-hour study drug infusion at 2, 4, 6, and 8 weeks.
Statistical Analysis
PVR and mPAP were analyzed using parametric analysis of variance with effects for treatment and center. Other efficacy variables were analyzed using analysis of covariance with main effect for treatment and the baseline as a covariate. Demographic characteristics, vital signs, and plasma concentrations of levosimendan and its metabolites were summarized by treatment group using descriptive statistics.
RESULTS
A total of 28 Caucasian patients with pulmonary hypertension (18 in the levosimendan and 10 in the placebo group) participated in the study. Baseline characteristics are described in Table I.
|
|
The absolute values of PVR and other hemodynamic parameters before the study drug infusion at 8 weeks were unchanged compared with those at baseline (data not shown). The profiles of the relative PVR response to levosimendan or placebo at week 8 were similar to those during the initial 24-hour infusion period. The percentage reduction in PVR from baseline was numerically greater in the levosimendan group at all time points during the 6-hour infusion compared with placebo, reaching statistical significance only at the 4-hour time point (P = .042).
Steady-state concentrations of levosimendan within the therapeutic dose range were achieved by 6 hours and were maintained throughout the duration of the 24-hour infusion. Levosimendan disappeared rapidly from plasma after cessation of the 24-hour infusion, whereas the maximum concentration of the active metabolite, OR-1896, was attained 2 to 4 days later (5 ng/mL) and was still detectable in the plasma of 8 of 15 patients at 2 weeks (overall mean level = 0.82 ± 1.2 ng/mL). Mean levels of OR-1896 did not exceed 1.0 mg/mL during the remainder of the study, despite the repeated treatment cycles.
Greater increases in heart rate and decreases in blood pressure were observed in the levosimendan group than in the placebo group during the 24-hour infusion. Mean heart rate increased from baseline in the levosimendan group by a maximum of 8.5 ± 11 bpm at the 8-hour time point, whereas in the placebo group, the maximum increase in mean rate was 4.0 ± 6.4 bpm at the 2-hour time point. There was a decrease from baseline in systolic blood pressure in the levosimendan group during the first 24 hours, with the maximum decrease of 16 ± 19 mm Hg occurring at the 24-hour time point. In the placebo group, systolic blood pressure increased up to a maximum of 6.2 ± 8.9 mm Hg at the 6-hour time point. Although the broad patterns of blood pressure and heart rate responses were similar during the subsequent 6-hour infusion periods, no consistent statistically significant differences were observed between the treatment groups.
Safety
All patients completed the initial 24-hour study drug infusion period. One patient randomized to levosimendan discontinued the study prematurely because of prolonged hypotension, which started 20 minutes after completing the 24-hour infusion. Another patient withdrew consent at 2 months.
Two patients discontinued placebo because of adverse events. One patient died 10 days after completing the 24-hour infusion as a result of progression of heart failure and acute kidney failure. Another patient discontinued the study after the third treatment cycle because of a dermal infection of the thoracic wall and associated edema.
A total of 65 adverse events were recorded in 19 patients (levosimendan, n = 11 [61%]; placebo, n = 8 [80%]). Ten of these events occurred during the initial 24-hour infusion (levosimendan, n = 8 [44%]; placebo, n = 2 [20%]); 7 adverse events were recorded during days 1 to 14, and the remainder occurred between days 14 and 84.
Hypotension, defined as systolic blood pressure less than 85 mm Hg for longer than 10 minutes, was the most often reported adverse event with levosimendan, and 8 episodes were experienced by 4 patients in the levosimendan group. Hypotension led to dose reduction in 3 of these patients. No patient in the placebo group experienced hypotension. Headache was reported by 4 patients (levosimendan, n = 3 [17%]; placebo, n = 1 [10%]). A similar proportion of patients in the levosimendan and placebo groups reported drug-related or serious adverse events, 33% and 30%, respectively.
DISCUSSION
In this first placebo-controlled study in patients with pulmonary hypertension of diverse causes, we investigated (1) whether levosimendan lowers PVR and PAP, (2) whether repeated dosing of levosimendan is well tolerated and the dosing regimen appropriate, and (3) whether any treatment effect was compromised by the development of tolerance. The results provided assurance on all these points.
Initial administration of levosimendan resulted in a significant decrease in PVR and PAP from baseline to 24 hours compared with placebo. The change in PVR at 8 weeks after the fifth cycle of treatment was similar to the initial treatment, indicating no development of tolerance to the regimen. Patients' clinical status was not subject to formal monitoring, but no overt deteriorations were apparent between the repeated infusions, suggesting that there was no clinically relevant rebound of the recorded hemodynamic effects. This is supported by the fact that no use of rescue medication for pulmonary hypertension was required during the study.
The study population had several distinctive characteristics (Table I). All had advanced heart failure (NYHA class III or IV), and most (75%) had signs of overt right heart failure, with jugular venous distension and/or peripheral edema. Moreover, all patients had a previous positive response to invasive vasodilator testing. Our results are consistent with other preliminary data in patients with pulmonary venous hypertension20 and extend earlier evidence for beneficial hemodynamic effects of levosimendan—including a reduction in PAP—in patients with severe left heart failure16-18 or myocardial infarction26 to patients with right heart failure and pulmonary arterial hypertension. Whether and to what extent these effects can be replicated in patients with a different clinical presentation of pulmonary hypertension remains to be determined. Fourteen of our patients had pulmonary venous hypertension due to left-sided heart disease. The current guidelines do not give clear treatment advice, and no drug is licensed for these patients. Given the profile of levosimendan, this group could even be one of the major target populations for this drug. The dual mechanism of action of levosimendan, comprising calcium sensitization of myofilaments by binding to troponin C8-12 plus the opening of ATP-dependent potassium channels,13-15 has theoretical advantages over some other drugs currently used for pulmonary hypertension. In particular, levosimendan exerts positive inotropic effects in the myocardium, in contrast to calcium-channel blockers, and decreases PAP through a different mechanism than with current therapy.13-15
Whereas levosimendan decreased PVR and PAP, both these indices (PVR especially) increased in placebo-treated patients. These increases may, in part, be explained by the distress of patients undergoing hemodynamic monitoring in an intensive care unit (we did not instrument our patients 24 or 48 hours before the measurements were taken). Similar increases in PAP in placebo-treated patients have been reported in a previous study.17 The results of the present study may therefore be interpreted as an indication of the capacity of levosimendan to prevent an increase in PVR and PAP during stressful situations.
Reduction in systemic pressures is a potential effect of vasodilators in patients with pulmonary hypertension. Our observations and experience suggest that with prudent dosing and careful observation, the possibility of this effect need not be a barrier to the use of levosimendan in pulmonary hypertension. Should they occur, falls in systemic blood pressure can be managed by correcting preload with an infusion of saline, as was the case in our cohort. Six of the 8 episodes of hypotension noted during this study were asymptomatic and relatively short lasting (3 hours).
The interpretation of the results was hampered by the small sample size and the failure to capture circadian changes in baseline hemodynamics. Limited patient numbers may have contributed to the absence of any discernible effect on clinical indices such as rehospitalizations, days out of hospital, or exercise capacity. Nevertheless, we were able to demonstrate that levosimendan was effective in the treatment of pulmonary hypertension. We examined only 1 dosing regimen and therefore cannot rule out that a more frequent dosing interval or a longer infusion time could have been more efficacious. Plasma levels of the levosimendan active metabolite OR-1896 had declined to very low levels by the end of the 14-day intertreatment intervals, which suggests that either a higher total dose of levosimendan or shorter dosing interval might be advantageous. Beneficial effects of serial levosimendan treatment have been reported in patients with advanced heart failure.27
The plasma concentrations and concentration-time profiles of both levosimendan and its active metabolite in this pulmonary hypertension study were similar to those seen in chronic heart failure.18,22,23
Overall, levosimendan was well tolerated in the study, and no unexpected or previously undocumented adverse events were identified. However, this overall conclusion on safety and tolerability must be qualified by an acknowledgment of the scale of the study.
In conclusion, levosimendan proved efficacious in the treatment of patients with pulmonary hypertension of various etiologies. Continued efficacy was evident with repeated dosing, without any apparent development of tolerance. We postulate that a higher dose or shorter dosing interval could have been even more effective. Larger studies of levosimendan are warranted to establish the optimal use of levosimendan in patients with overt right heart failure and low blood pressure and in patients with excessively high PVR prohibiting heart transplantation.
ACKNOWLEDGEMENTS
Study sites: Unfallkrankenhaus Berlin, Academic Teaching Hospital, Charité Medical School Berlin, Germany; Christian-Albrechts-Universität, Klinik für Herz- und Gefäßchirurgie Kiel, Germany; Universitätsklinikum Heidelberg, Abteilung Innere Medizin III, Heidelberg, Germany; Akademiska hospital, OTM division, Kardiologi, Uppsala, Sweden; Ernst-Moritz-Arndt-Universität, Zentrum für Innere Medizin, Greifswald, Germany.
Financial disclosure: Matti Kivikko, Pasi Pohjanjousi, and Tiina Petterson are employees of Orion Pharma, the company that manufactures levosimendan.
REFERENCES
1. Peacock AJ. Treatment of pulmonary hypertension. BMJ. 2003;326: 835-836.
2. McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension [published correction appears in Eur Respir J. 2005;25:942]. Eur Respir J. 2005;25: 244-249.
3. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174: 1257-1263.
4. Barst RJ, Langleben D, Badesch D, et al; STRIDE-2 Study Group. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol. 2006;47: 2049-2056.
5. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension [published correction appears in N Engl J Med. 2006;354:2400-2401]. N Engl J Med. 2005;353: 2148-2157.
6. Badesch DB, Abman SH, Ahearn GS, et al; American College of Chest Physicians. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1 suppl): 35S-62S.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
7. Simonneau G, Barst RJ, Galie N, et al; Treprostinil Study Group. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165: 800-804.
8. Pollesello P, Ovaska M, Kaivola J, et al. Binding of a new Casensitizer, levosimendan, to recombinant human cardiac troponin C: a molecular modelling, fluorescence probe and proton nuclear magnetic resonance study. J Biol Chem. 1994;269: 28584-28590.
9. Edes I, Kiss E, Kitada Y, et al. Effects of levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart. Circ Res. 1995;77: 107-113.
10. Haikala H, Lindén I-B. Mechanism of action of calcium-sensitizing drugs. J Cardiovasc Pharmacol. 1995;26(suppl 1): S10-S19.[Web of Science][Medline] [Order article via Infotrieve]
11. Haikala H, Kaivola J, Nissinen E, Wall P, Levijoki J, Linden IB. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J Mol Cell Cardiol. 1995;27: 1859-1866.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12. Levijoki J, Pollesello P, Kaivola J, et al. Further evidence for the cardiac troponin C mediated calcium sensitization by levosimendan: structure-response and binding analysis with analogs of levosimendan. J Mol Cell Cardiol. 2000;32: 479-491.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. Pataricza J, Hohn J, Petri A, Balogh A, Papp JG. Comparison of the vasorelaxing effect of cromakalim and the new inodilator, levosimendan, in human isolated portal vein. J Pharm Pharmacol. 2002;52: 213-217.
14. Kaheinen P, Pollesello P, Levijoki J, Haikala H. Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels. J Cardiovasc Pharmacol. 2001;37: 367-374.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
15. Yokoshiki H, Katsube Y, Sunagawa M, Sperelakis N. Levosimendan, a novel Ca2+ sensitizer, activates the glibenclamide-sensitive K+ channel in rat arterial myocytes. Eur J Pharmacol. 1997;333: 249-259.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
16. Nieminen MS, Akkila J, Hasenfuss G, et al. Haemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol. 2000;36: 1903-1912.
17. Slawsky MT, Colucci WS, Gottlieb SS, et al. Acute haemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation. 2000;102: 2222-2227.
18. Kivikko M, Lehtonen L, Colucci WS. Sustained haemodynamic effects of intravenous levosimendan. Circulation. 2003;107: 81-86.
19. 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: 196-202.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Costard-Jäckle A, Fischer B, Haake N, et al. Severe pulmonary hypertension in endstage heart failure: impressive reduction of transpulmonary gradient with levosimendan [abstract]. Eur J Heart Fail. 2003;2(suppl): 151-152.[CrossRef]
21. Sandell EP, Häyhä M, Antila S, et al. Pharmacokinetics of levosimendan in healthy volunteers and patients with congestive heart failure. J Cardiovasc Pharmacol. 1995;26(suppl 1): S57-S62.[Web of Science][Medline] [Order article via Infotrieve]
22. Kivikko M, Antila S, Eha J, Lehtonen L, Pentikäinen PJ. 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: 465-471.[Web of Science][Medline] [Order article via Infotrieve]
23. Kivikko M, Antila S, Eha J, Lehtonen L, Pentikäinen PJ. Pharmacodynamics and safety of a new calcium sensitizer, levosimendan, and its metabolites during an extended infusion in patients with severe heart failure. J Clin Pharmacol. 2002;42: 43-51.[Abstract]
24. Simonneau G, Galiè N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43(suppl S): 5S-12S.
25. Puttonen J, Kantele S, Ruck A, Ramela M, Häkkinen S, Kivikko M, Pentikäinen P. Pharmacokinetics of intravenous levosimendan and its metabolites in subjects with hepatic impairment. J Clin Pharmacol. 2008;48(4): 445-454.
26. Sonntag S, Sundberg S, Lehtonen L, Kleber FX. The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia. J Am Coll Cardiol. 2004;43: 2177-2182.
27. Parissis JT, Adamopoulos S, Farmakis D, et al. Effects of serial levosimendan infusions on left ventricular performance and plasma biomarkers of myocardial injury and neurohormonal and immune activation in patients with advanced heart failure. Heart. 2006;92: 1768-1772.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
