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Inotropic agents in advanced heart failure: Repetita iuvant?
International Journal of Cardiology 176 (2014) 6–7
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Editorial
Inotropic agents in advanced heart failure: Repetita iuvant? Leonardo De Luca ⁎ Department of Cardiovascular Sciences, European Hospital, Via Portuense 700, 00149 Rome, Italy
a r t i c l e
i n f o
Article history: Received 2 May 2014 Accepted 29 June 2014 Available online 5 July 2014 Keywords: Inotropic agents Advanced heart failure Levosimendan
Repetita iuvant is a Latin expression that means “repeating things help” or in a sense are useful. This method may assist in not only learning an information, but also in enhancing the effect of an action. Some patients admitted with chronic advanced heart failure (HF) receive repeated or intermittent infusions of positive inotropes in an effort to improve cardiac performance, promote clinical stability, prevent rehospitalization and possibly improve outcome [1]. Although this treatment strategy is widely adopted with conventional inotropic agents, it is worth to highlight that there are no randomized, controlled studies on intermittent infusions of dopamine or milrinone [2]. A randomized, controlled trial (the Randomized Outpatient Milrinone Evaluation [ROME] trial) studying the effects of intermittent outpatient infusions of milrinone has been terminated after enrollment of approximately 100 patients, and no data on the results have been published. On the other hand, several studies have tested the use of repetitive doses of dobutamine producing conflicting results and raising questions of whether the type of intermittency can influence the clinical effects of the inotropic support (Table 1) [3–9]. Notably, in the most numerous but unpublished study by Dies et al. [4] the repetitive use of dobutamine increased treadmill times, improved symptom scores and also increased mortality compared to placebo group (44% vs 17%) and has been stopped earlier by the Safety Event Committee. Levosimendan is indicated for the short-term treatment of acutely decompensated severe chronic HF in situations where conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate [1,10,11]. During the last decade, various independent research groups have published small-scale investigator-initiated
⁎ Tel.: +39 06 65975725; fax: +39 06 65975714. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ijcard.2014.06.063 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
studies, in which levosimendan has been administered repeatedly to patients with advanced chronic HF [12]. In this issue of the Journal, a panel consisting of 30 experts from 15 countries reviewed the literature regarding the repetitive use of levosimendan that includes 9 studies (6 of them are randomized) [13]. As also stated by the authors, it is challenging to derive definite conclusions based on the results of these studies for several reasons: (1) the small numbers of patients enrolled in each of these trials only allow detection of large differences between the treatment and control groups; (2) the infusion patterns (dosages and time intervals) varied widely between trials; (3) selection of primary and secondary outcome measures differed across protocols; (4) patient populations were not always comparable among studied; (5) control arm was heterogeneous (e.g., placebo, diuretics, dobutamine) and (6) follow-up duration varied between trials. The largest study with repetitive dosing with levosimendan (6-h infusions of 0.2 mg/kg/min every 2 weeks for 8 weeks) is the LevoRep (randomized trial investigating the efficacy and safety of pulsed infusions of levosimendan in outpatients with advanced heart failure), a randomized, double-blind, placebo-controlled study in advanced chronic HF [14]. At the end of the 24-week follow-up, the primary endpoint has not been reached, despite a non-significant positive trend in favor of levosimendan [15]. Therefore, at this point in time, any conclusion based on a single study of repeated levosimendan use should only be taken as hypothesis generating. Nevertheless, in the consensus document published in this issue of the Journal, the authors also performed a meta-analysis of the mortality data based on 7 studies (less than 350 patients, with 24 events in levosimendan and 49 in the comparator group) suggesting a benefit of repetitive use of levosimendan in terms of survival [13]. However, only the study by Nanas et al. [16] that contributed for 44% of the events in their calculation, clearly suggested a benefit in terms of mortality. Notably, this prospective trial was open label and the treatment assignment was not randomized, but instead sequential. In another recent meta-analysis [17] the mortality benefits were still significantly in favor of levosimendan although they did not introduce in their calculation the data of Nanas et al. However, in the latter metaanalysis, the most numerous study (n = 80) that strongly influenced the outcome was unpublished [18]. Omitting this study with high risk of bias, the effect on mortality of levosimendan with respect to placebo was not statistically significant (RR = 0.56, 95% CI 0.29–1.08, p = 0.11) [17]. In this context, the suggestions given by the expert panel consensus on the patient groups that can be considered to potentially benefit from planned intermittent treatment with levosimendan and their
Editorial
7
Table 1 Studies on iintermittent infusions of dobutamine. Study
Dobutamine
Control
N.
Follow-up
Hemodynamic outcome
Clinical outcome
Leier et al. [3] Dies et al. [4] Erlemeier et al. [5]
IV infusion for 4 h weekly × 24 wk IV infusion for 48 h/wk × 24 wk 8 × 24 h infusion over a 4-wk period with at least 3 days in between IV infusion 4 days/wk × 3 wk Infusion for 48 h/wk × 6 mo
Matched Placebo 5% dextrose solution
26 60 20
24 wk 8 wk 3 days
↑ ↑↑ ↑↑
↑ ↓↓ –
Usual activity Optimal standard treatment
20 38
↑↑ –
– –
24-h infusion every 2 wk × 6 wk then every 3 wk × 6 mo
Placebo
19
6 wk 8 wk for CI; 6 mo for other outcomes 32 mo
–
–
Adamopooulos et al. [6] Oliva et al. [7] Elis et al. [8]
CI = cardiac index; IV = intravenous. ↑: improvement; ↓: worsening.
preliminary recommendations for this treatment strategy, derived from the available evidence and from clinical experience, appear extremely important [13]. Briefly, they suggest a ‘scheduled’ repeated administration of levosimendan in case of severe systolic dysfunction (ejection fraction b 35%), NYHA class IIIb–IV and/or INTERMACS levels 4, 5, and 6, repeated hospitalization or emergency department visits despite optimal treatment for HF. The recommended dose ranges from 0.05 μg/kg/min to 0.2 μg/kg/min, for 6 h to 24 h, every 2 weeks to 4 weeks, taking caution regarding the possible adverse effects of levosimendan on systolic blood pressure, arrhythmias, kidney function and electrolytes [13]. In conclusion, is it reasonable to argue that repetita iuvant, in the sense that repeated doses of levosimendan and conventional inotropic agents are useful and safe for patients with advanced HF? It seems clear that we need further evidence for changing our clinical practice and to increase our experience with intermittent use of inotropic agents, as repetition is one of the main principles of the scientific method. In this direction, three studies has been started and long-awaited: the Intermittent Intravenous Levosimendan in Ambulatory Advanced Chronic Heart Failure Patients study (LION-HEART, NCT01536132), the Randomized, Double-Blind, Placebo Controlled, Multicenter Trial to Study Efficacy, Security, and Long Term Effects of Intermittent Repeated Levosimendan Administration in Patients with Advanced Heart Failure (LAICA, NCT00988806), and the Early LEvosimendan Vs Usual Care in Advanced Chronic hearTfailurE (ELEVATE, NCT01290146). Conflict of interest: none. References [1] McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–847. [2] Bayram M, De Luca L, Massie MB, Gheorghiade M. Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes. Am J Cardiol 2005;96(6A):47G–58G.
[3] Leier CV, Huss P, Lewis RP, Unverferth DV. Drug-induced conditioning in congestive heart failure. Circulation 1982;65:1382–7. [4] Dies F, Krell MJ, Whitlow P. Intermittent dobutamine in ambulatory outpatients with chronic cardiac failure. Circulation 1986;74(Suppl. II):II–38. [5] Erlemeier HH, Kupper W, Bleifeld W. Intermittent infusion of dobutamine in the therapy of severe congestive heart failure: long-term effects and lack of tolerance. Cardiovasc Drugs Ther 1992;6:391–8. [6] Adamopoulos S, Piepoli M, Qiang F, et al. Effects of pulsed beta-stimulant therapy on beta-adrenoceptors and chronotropic responsiveness in chronic heart failure. Lancet 1995;345:344–9. [7] Oliva F, Latini R, Politi A, et al. Intermittent 6-month low-dose dobutamine infusion in severe heart failure: DICE multicenter trial. Am Heart J 1999;138:247–53. [8] Elis A, Bental T, Kimchi O, Ravid M, Lishner M. Intermittent dobutamine treatment in patients with chronic refractory congestive heart failure: a randomized, doubleblind, placebo-controlled study. Clin Pharmacol Ther 1998;63:682–5. [9] Rapezzi C, Bracchetti G, Branzi A, Magnani B. The case against outpatient parenteral inotropic therapy for advanced heart failure. J Heart Lung Transplant 2000;19: S58–63. [10] De Luca L, Mebazaa A, Filippatos G, et al. Overview of emerging pharmacologic agents for acute heart failure syndromes. Eur J Heart Fail 2008;10:201–13. [11] De Luca L, Colucci WS, Nieminen MS, Massie BM, Gheorghiade M. Evidence-based use of levosimendan in different clinical settings. Eur Heart J 2006;27:1908–20. [12] Nieminen MS, Fruhwald S, Heunks LM, et al. Levosimendan: current data, clinical use and future development. Heart Lung Vessel 2013;5:227–45. [13] Nieminen MS, Altenberger J, Ben-Gal T, et al. Repetitive use of levosimendan for treatment of chronic advanced heart failure: clinical evidence, practical considerations, and perspectives: an expert panel consensus. Int J Cardiol 2014;174:360–7. [14] Altenberger J, Parissis JT, Ulmer H, Poelzl G, LevoRep Investigators. Rationale and design of the multicentre randomized trial investigating the efficacy and safety of pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep study). Eur J Heart Fail 2010;12:186–92. [15] Poelzl G. Efficacy and safety of intermittent ambulatory infusion of levosimendan in endstage heart failure. At “Special session, Latest Updates”/Heart Failure 2013 congress of the ESC-HFA, Lisbon; May 27, 2013. [16] Nanas JN, Papazoglou P, Tsagalou EP, et al. Efficacy and safety of intermittent, longterm, concomitant dobutamine and levosimendan infusions in severe heart failure refractory to dobutamine alone. Am J Cardiol 2005;95:768–71. [17] Silvetti S, Greco T, Di Prima AL, et al. Intermittent levosimendan improves mid-term survival in chronic heart failure patients: meta-analysis of randomised trials. Clin Res Cardiol 2014;103:505–13. [18] Levin R, Porcile R, Tanus E, Degrange M. Abstract 3815: the intermittent infusion of levosimendan reduces mortality and re-admissions in patients with advanced heart failure. Circulation 2009;120:S865.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Editorial
Inotropic agents in advanced heart failure: Repetita iuvant? Leonardo De Luca ⁎ Department of Cardiovascular Sciences, European Hospital, Via Portuense 700, 00149 Rome, Italy
a r t i c l e
i n f o
Article history: Received 2 May 2014 Accepted 29 June 2014 Available online 5 July 2014 Keywords: Inotropic agents Advanced heart failure Levosimendan
Repetita iuvant is a Latin expression that means “repeating things help” or in a sense are useful. This method may assist in not only learning an information, but also in enhancing the effect of an action. Some patients admitted with chronic advanced heart failure (HF) receive repeated or intermittent infusions of positive inotropes in an effort to improve cardiac performance, promote clinical stability, prevent rehospitalization and possibly improve outcome [1]. Although this treatment strategy is widely adopted with conventional inotropic agents, it is worth to highlight that there are no randomized, controlled studies on intermittent infusions of dopamine or milrinone [2]. A randomized, controlled trial (the Randomized Outpatient Milrinone Evaluation [ROME] trial) studying the effects of intermittent outpatient infusions of milrinone has been terminated after enrollment of approximately 100 patients, and no data on the results have been published. On the other hand, several studies have tested the use of repetitive doses of dobutamine producing conflicting results and raising questions of whether the type of intermittency can influence the clinical effects of the inotropic support (Table 1) [3–9]. Notably, in the most numerous but unpublished study by Dies et al. [4] the repetitive use of dobutamine increased treadmill times, improved symptom scores and also increased mortality compared to placebo group (44% vs 17%) and has been stopped earlier by the Safety Event Committee. Levosimendan is indicated for the short-term treatment of acutely decompensated severe chronic HF in situations where conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate [1,10,11]. During the last decade, various independent research groups have published small-scale investigator-initiated
⁎ Tel.: +39 06 65975725; fax: +39 06 65975714. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ijcard.2014.06.063 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
studies, in which levosimendan has been administered repeatedly to patients with advanced chronic HF [12]. In this issue of the Journal, a panel consisting of 30 experts from 15 countries reviewed the literature regarding the repetitive use of levosimendan that includes 9 studies (6 of them are randomized) [13]. As also stated by the authors, it is challenging to derive definite conclusions based on the results of these studies for several reasons: (1) the small numbers of patients enrolled in each of these trials only allow detection of large differences between the treatment and control groups; (2) the infusion patterns (dosages and time intervals) varied widely between trials; (3) selection of primary and secondary outcome measures differed across protocols; (4) patient populations were not always comparable among studied; (5) control arm was heterogeneous (e.g., placebo, diuretics, dobutamine) and (6) follow-up duration varied between trials. The largest study with repetitive dosing with levosimendan (6-h infusions of 0.2 mg/kg/min every 2 weeks for 8 weeks) is the LevoRep (randomized trial investigating the efficacy and safety of pulsed infusions of levosimendan in outpatients with advanced heart failure), a randomized, double-blind, placebo-controlled study in advanced chronic HF [14]. At the end of the 24-week follow-up, the primary endpoint has not been reached, despite a non-significant positive trend in favor of levosimendan [15]. Therefore, at this point in time, any conclusion based on a single study of repeated levosimendan use should only be taken as hypothesis generating. Nevertheless, in the consensus document published in this issue of the Journal, the authors also performed a meta-analysis of the mortality data based on 7 studies (less than 350 patients, with 24 events in levosimendan and 49 in the comparator group) suggesting a benefit of repetitive use of levosimendan in terms of survival [13]. However, only the study by Nanas et al. [16] that contributed for 44% of the events in their calculation, clearly suggested a benefit in terms of mortality. Notably, this prospective trial was open label and the treatment assignment was not randomized, but instead sequential. In another recent meta-analysis [17] the mortality benefits were still significantly in favor of levosimendan although they did not introduce in their calculation the data of Nanas et al. However, in the latter metaanalysis, the most numerous study (n = 80) that strongly influenced the outcome was unpublished [18]. Omitting this study with high risk of bias, the effect on mortality of levosimendan with respect to placebo was not statistically significant (RR = 0.56, 95% CI 0.29–1.08, p = 0.11) [17]. In this context, the suggestions given by the expert panel consensus on the patient groups that can be considered to potentially benefit from planned intermittent treatment with levosimendan and their
Editorial
7
Table 1 Studies on iintermittent infusions of dobutamine. Study
Dobutamine
Control
N.
Follow-up
Hemodynamic outcome
Clinical outcome
Leier et al. [3] Dies et al. [4] Erlemeier et al. [5]
IV infusion for 4 h weekly × 24 wk IV infusion for 48 h/wk × 24 wk 8 × 24 h infusion over a 4-wk period with at least 3 days in between IV infusion 4 days/wk × 3 wk Infusion for 48 h/wk × 6 mo
Matched Placebo 5% dextrose solution
26 60 20
24 wk 8 wk 3 days
↑ ↑↑ ↑↑
↑ ↓↓ –
Usual activity Optimal standard treatment
20 38
↑↑ –
– –
24-h infusion every 2 wk × 6 wk then every 3 wk × 6 mo
Placebo
19
6 wk 8 wk for CI; 6 mo for other outcomes 32 mo
–
–
Adamopooulos et al. [6] Oliva et al. [7] Elis et al. [8]
CI = cardiac index; IV = intravenous. ↑: improvement; ↓: worsening.
preliminary recommendations for this treatment strategy, derived from the available evidence and from clinical experience, appear extremely important [13]. Briefly, they suggest a ‘scheduled’ repeated administration of levosimendan in case of severe systolic dysfunction (ejection fraction b 35%), NYHA class IIIb–IV and/or INTERMACS levels 4, 5, and 6, repeated hospitalization or emergency department visits despite optimal treatment for HF. The recommended dose ranges from 0.05 μg/kg/min to 0.2 μg/kg/min, for 6 h to 24 h, every 2 weeks to 4 weeks, taking caution regarding the possible adverse effects of levosimendan on systolic blood pressure, arrhythmias, kidney function and electrolytes [13]. In conclusion, is it reasonable to argue that repetita iuvant, in the sense that repeated doses of levosimendan and conventional inotropic agents are useful and safe for patients with advanced HF? It seems clear that we need further evidence for changing our clinical practice and to increase our experience with intermittent use of inotropic agents, as repetition is one of the main principles of the scientific method. In this direction, three studies has been started and long-awaited: the Intermittent Intravenous Levosimendan in Ambulatory Advanced Chronic Heart Failure Patients study (LION-HEART, NCT01536132), the Randomized, Double-Blind, Placebo Controlled, Multicenter Trial to Study Efficacy, Security, and Long Term Effects of Intermittent Repeated Levosimendan Administration in Patients with Advanced Heart Failure (LAICA, NCT00988806), and the Early LEvosimendan Vs Usual Care in Advanced Chronic hearTfailurE (ELEVATE, NCT01290146). Conflict of interest: none. References [1] McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–847. [2] Bayram M, De Luca L, Massie MB, Gheorghiade M. Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes. Am J Cardiol 2005;96(6A):47G–58G.
[3] Leier CV, Huss P, Lewis RP, Unverferth DV. Drug-induced conditioning in congestive heart failure. Circulation 1982;65:1382–7. [4] Dies F, Krell MJ, Whitlow P. Intermittent dobutamine in ambulatory outpatients with chronic cardiac failure. Circulation 1986;74(Suppl. II):II–38. [5] Erlemeier HH, Kupper W, Bleifeld W. Intermittent infusion of dobutamine in the therapy of severe congestive heart failure: long-term effects and lack of tolerance. Cardiovasc Drugs Ther 1992;6:391–8. [6] Adamopoulos S, Piepoli M, Qiang F, et al. Effects of pulsed beta-stimulant therapy on beta-adrenoceptors and chronotropic responsiveness in chronic heart failure. Lancet 1995;345:344–9. [7] Oliva F, Latini R, Politi A, et al. Intermittent 6-month low-dose dobutamine infusion in severe heart failure: DICE multicenter trial. Am Heart J 1999;138:247–53. [8] Elis A, Bental T, Kimchi O, Ravid M, Lishner M. Intermittent dobutamine treatment in patients with chronic refractory congestive heart failure: a randomized, doubleblind, placebo-controlled study. Clin Pharmacol Ther 1998;63:682–5. [9] Rapezzi C, Bracchetti G, Branzi A, Magnani B. The case against outpatient parenteral inotropic therapy for advanced heart failure. J Heart Lung Transplant 2000;19: S58–63. [10] De Luca L, Mebazaa A, Filippatos G, et al. Overview of emerging pharmacologic agents for acute heart failure syndromes. Eur J Heart Fail 2008;10:201–13. [11] De Luca L, Colucci WS, Nieminen MS, Massie BM, Gheorghiade M. Evidence-based use of levosimendan in different clinical settings. Eur Heart J 2006;27:1908–20. [12] Nieminen MS, Fruhwald S, Heunks LM, et al. Levosimendan: current data, clinical use and future development. Heart Lung Vessel 2013;5:227–45. [13] Nieminen MS, Altenberger J, Ben-Gal T, et al. Repetitive use of levosimendan for treatment of chronic advanced heart failure: clinical evidence, practical considerations, and perspectives: an expert panel consensus. Int J Cardiol 2014;174:360–7. [14] Altenberger J, Parissis JT, Ulmer H, Poelzl G, LevoRep Investigators. Rationale and design of the multicentre randomized trial investigating the efficacy and safety of pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep study). Eur J Heart Fail 2010;12:186–92. [15] Poelzl G. Efficacy and safety of intermittent ambulatory infusion of levosimendan in endstage heart failure. At “Special session, Latest Updates”/Heart Failure 2013 congress of the ESC-HFA, Lisbon; May 27, 2013. [16] Nanas JN, Papazoglou P, Tsagalou EP, et al. Efficacy and safety of intermittent, longterm, concomitant dobutamine and levosimendan infusions in severe heart failure refractory to dobutamine alone. Am J Cardiol 2005;95:768–71. [17] Silvetti S, Greco T, Di Prima AL, et al. Intermittent levosimendan improves mid-term survival in chronic heart failure patients: meta-analysis of randomised trials. Clin Res Cardiol 2014;103:505–13. [18] Levin R, Porcile R, Tanus E, Degrange M. Abstract 3815: the intermittent infusion of levosimendan reduces mortality and re-admissions in patients with advanced heart failure. Circulation 2009;120:S865.