Levosimendan efficacy and safety : 20 Years of SIMDAX in clinical use

Downloaded from https://journals.lww.com/cardiovascularpharm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3z484KQalTVFxlEAbWg8lLDBn+vfkHmriHTJp1HCIfaE= on 07/09/2020 Downloaded from https://journals.lww.com/cardiovascularpharm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3z484KQalTVFxlEAbWg8lLDBn+vfkHmriHTJp1HCIfaE= on 07/09/2020 PERSPECTIVES Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use Zoltán Papp, MD, PhD, 1 Piergiuseppe Agostoni, MD, PhD, 2 Julian Alvarez, MD, PhD, 3 Dominique Bettex, MD, PhD, 4 Stefan Bouchez, MD, PhD, 5 Dulce Brito, MD, PhD, 6 Vladimir  Cerný, MD, PhD, 7 Josep Comin-Colet, MD, PhD, 8 Marisa G. Crespo-Leiro, MD, PhD, 9 Juan F. Delgado, MD, PhD, 10 István Édes, MD, PhD, 1 Alexander A. Eremenko, MD, PhD, 11 Dimitrios Farmakis, MD, PhD, 12 Francesco Fedele, MD, PhD, 13 Cândida Fonseca, MD, PhD, 14 Sonja Fruhwald, MD, PhD, 15 Massimo Girardis, MD, PhD, 16 Fabio Guarracino, MD, PhD, 17 Veli-Pekka Harjola, MD, PhD, 18 Matthias Heringlake, MD, PhD, 19 Antoine Herpain, MD, PhD, 20 Leo M. A. Heunks, MD, PhD, 21 Tryggve Husebye, MD, PhD, 22 Vi snja Ivancan, MD, PhD, 23 Kristjan Karason, MD, PhD, 24 Sundeep Kaul, MD, PhD, 25 Matti Kivikko, MD, PhD, 26 Janek Kubica, MD, PhD, 27 Josep Masip, MD, PhD, 28 Simon Matskeplishvili, MD, PhD, 29 Alexandre Mebazaa, MD, PhD, 30 Markku S. Nieminen, MD, PhD, 31 Fabrizio Oliva, MD, PhD, 32 Julius G. Papp, MD, PhD, 33 John Parissis, MD, PhD, 34 Alexander Parkhomenko, MD, PhD, 35 Pentti Põder, MD, PhD, 36 Gerhard Pölzl, MD, PhD, 37 Alexander Reinecke, MD, PhD, 38 Sven-Erik Ricksten, MD, PhD, 39 Hynek Riha, MD, PhD, 40 Alain Rudiger, MD, PhD, 41 Toni Sarapohja, PhD, 42 Robert H. G. Schwinger, MD, PhD, 43 Wolfgang Toller, MD, PhD, 44 Luigi Tritapepe, MD, PhD, 45 Carsten Tschöpe, MD, PhD, 46 Gerhard Wikström, MD, PhD, 47 Dirk von Lewinski, MD, PhD, 48 Bojan Vrtovec, MD, PhD, 49 and Piero Pollesello, PhD 50 Abstract: Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate–dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years. Key Words: acute heart failure, advanced heart failure, hemodynamics, inodilator, inotrope, neurohormone, regulatory clinical trial (J Cardiovasc PharmacolÔ2020;76:4–22) ORIGINS OF A UNIQUE CARDIOVASCULAR AGENT Before the 1980s, therapy to enhance cardiac contractility in heart failure (HF) substantially meant oral digitalis glycosides, supplemented by beta-adrenergic agonists such as dopamine or dobutamine (introduced in the middle of the 1970s) in acute situations. 1 It was therefore a matter of some note when the US Food and Drug Administration approved a new agent as a shortterm IV therapy for patients with refractory HF. Amrinone was the product of a widespread research initiative that recognized the limitations of existing inotropic therapy and that, equipped with a new understanding of the cellular mechanisms of cardiac contractility, set out to develop what respected commentators of the time referred to as “non-glycoside, non-sympathomimetic positive inotropic agents.” 2–4 Amrinone was the first agent to reach clinical use from the small but important family of phosphodiesterase (PDE) inhibitors, which would later include milrinone and enoximone. 5,6 However, despite being nonsympathomimetic positive inotropic agents, all PDE inhibitors, in common with the catecholamines, were shown to be calcium mobilizers, probably due to their limited selectivity toward specifickey 4|www.jcvp.org J Cardiovasc PharmacoläVolume 76, Number 1, July 2020 PDE isoforms, and shared with catecholamines some unwanted effects intrinsic to any drug that raises intracellular calcium. In fact, all calcium mobilizers, by definition, exert an inotropic effect by providing increased ionic calcium levels for the contractile protein machinery, a process that may ultimately prove detrimental to individual cardiomyocytes and therefore also to patients. 7 At about the same time, a new concept was proposed by the independent groups of J Caspar Rüegg in Heidelberg and R. John Solaro in Chicago, namely the potential of new agents to enhance the sensitivity to calcium of key targets in the contractile apparatus instead of increasing the intracellular calcium transient to augment contractility. 8,9 In 1984, Rüegg et al 10 described the pharmacology of a new agent, later known as pimobendan, which combined PDE inhibitor activity with a direct calcium-sensitizing effect. It was in this climate of innovation that the new chemical entity R-((4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3pyridazinyl)phenyl)hydrazono)propanedinitrile, known by the identifier OR-1259 at the time, appeared in the published records. An abstract was published in 1992 describing “a positive inotropic and vasodilatory compound with antiarrhythmic properties.” 11 This preliminary report noted that OR-1259 exerted a positive inotropic effect despite a reduction in the voltage-sensitive Ca 2+ current. As is not uncommon in abstract reports, the authors advised that “Further studies.are in progress.” In 1995, Heimo Haikala reported the findings of indepth research into the mechanism of action of this agent in his pioneering paper. 12 At the same time, an article describing the binding of a new Ca 2+ sensitizer, levosimendan, to recombinant human cardiac troponin C was also published. 13 Those first descriptions may be regarded as foundation publications in the chronology of this drug and a starting point for the PubMed-cited literature on levosimendan, which had expanded to almost 1500 reports by the end of 2019. Levosimendan was described as “a calcium sensitiser rationally designed and screened to act through its calcium-dependent binding to cardiac troponin C,”and the experimental basis for this description was set out in detail. 12 From the beginning, clear mechanistic differences were spotted between levosimendan and several other drugs then in development, including pimobendan, MCI-154, and EMD 53998. Levosimendan was a first-in-class agent at the time of its emergence, promoting inotropy mainly through calcium sensitization of cardiac troponin C (cTnC). More than 20 years later it remains, remarkably, an only-inclass drug, with a mechanism of action that clearly differentiates it from adrenergic agents. From the 1 Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; 2 Department of Clinical Sciences and Community Health, Centro Cardiologico Monzino, IRCCS, Milan, Italy; 3 Department of Surgery, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain; 4 Institute of Anaesthesiology, University Hospital of Zurich, Zurich, Switzerland; 5 Department of Anaesthesiology, University Hospital, Ghent, Belgium; 6 Cardiology Department, Centro Hospitalar Universitario Lisboa Norte, CCUI, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; 7 Department of Anaesthesiology, Perioperative Medicine and Intensive Care, Masaryk Hospital, J.E. Purkinje University, Usti nad Labem, Czech Republic; 8 Heart Diseases Institute, Hospital Universitari de Bellvitge, Barcelona, Spain; 9 Complexo Hospitalario Universitario A Coruña (CHUAC), CIBERCV, Instituto de Investigacion Biomedica A Coruña (INIBIC), Universidad de a Coruña (UDC), La Coruña, Spain; 10 Heart Failure and Transplant Program, Cardiology Department, University Hospital 12 Octubre, Madrid, Spain; 11 Department of Cardiac Intensive Care, Petrovskii National Research Centre of Surgery, Sechenov University, Moscow, Russia; 12 Department of Cardiology, Medical School, University of Cyprus, Nicosia, Cyprus; 13 Department of Cardiovascular, Respiratory, Nephrology, Anaesthesiology and Geriatric Sciences, La Sapienza University of Rome, Rome, Italy; 14 Heart Failure Clinic, São Francisco Xavier Hospital, CHLO, Lisbon, Portugal; 15 Department of Anaesthesiology and Intensive Care Medicine, Division of Anaesthesiology for Cardiovascular Surgery and Intensive Care Medicine, Medical University of Graz, Graz, Austria; 16 Struttura Complessa di Anestesia 1, Policlinico di Modena, Modena, Italy; 17 Dipartimento di Anestesia e Terapie Intensive, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; 18 Emergency Medicine, Meilahti Central University Hospital, University of Helsinki, Helsinki, Finland; 19 Department of Anaesthesiology and Intensive Care Medicine, University of Lübeck, Lübeck, Germany; 20 Department of Intensive Care, Hôpital Erasme, Brussels, Belgium; 21 Department of Intensive Care Medicine, Amsterdam UMC, Amsterdam, the Netherlands; 22 Department of Cardiology, Oslo University Hospital Ullevaal, Oslo, Norway; 23 Department of Anaesthesiology, Reanimatology and Intensive Care, University Hospital Centre, Zagreb, Croatia; 24 Departments of Cardiology and Transplantation, Sahlgrenska University Hospital, Gothenburg, Sweden; 25 Intensive Care Unit, National Health Service, Leeds, United Kingdom; 26 Global Medical Affairs, R&D, Orion Pharma, Espoo, Finland; 27 Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Torun, Poland; 28 Intensive Care Department, Consorci Sanitari Integral, University of Barcelona, Barcelona, Spain; 29 Lomonosov Moscow State University Medical Centre, Moscow, Russia; 30 Department of Anaesthesiology and Critical Care Medicine, AP-HP, Saint Louis and Lariboisière University Hospitals, Paris, France; 31 Sydäntutkimussäätiö, Helsinki, Finland; 32 Department of Cardiology, Niguarda Ca’Granda Hospital, Milan, Italy; 33 MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary; 34 Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 35 Emergency Cardiology Department, National Scientific Centre MD Strazhesko Institute of Cardiology, Kiev, Ukraine; 36 Department of Cardiology, North Estonia Medical Centre, Tallinn, Estonia; 37 Department of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Austria; 38 Klinik für Innere Medizin III, Kardiologie, Universitätsklinikum Schleswig-Holstein, Kiel, Germany; 39 Department of Anaesthesiology and Intensive Care, Sahlgrenska University Hospital, Gothenburg, Sweden; 40 Department of Anaesthesiology and Intensive Care Medicine, Cardiothoracic Anaesthesiology and Intensive Care, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 41 Department of Medicine, Spittal Limmattal, Schlieren, Switzerland; 42 Statistical Services, R&D, Orion Pharma, Espoo, Finland; 43 Medizinische Klinik II, Klinikum Weiden, Teaching Hospital of University of Regensburg, Weiden, Germany; 44 Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Austria; 45 Anaesthesia and Intensive Care Division, San Camillo-Forlanini Hospital, Rome, Italy; 46 Department of Cardiology, Campus Virchow Klinikum, Charité— University Medicine Berlin, Berlin, Germany; 47 Institute of Medical Sciences, Uppsala University, Uppsala, Sweden; 48 Department of Cardiology, Myokardiale Energetik und Metabolismus Research Unit, Medical University of Graz, Graz, Austria; 49 Department of Cardiology, Advanced Heart Failure and Transplantation Centre, University Clinical Centre, Ljubljana, Slovenia; and 50 Critical Care Proprietary Products, Orion Pharma, Espoo, Finland. P. Pollesello, T. Sarapohja, and M. Kivikko are full-time or part-time employees of Orion Pharma. In the past 5 years, all other authors have received honoraria from Orion Pharma for educational lectures and/or unrestricted grants for investigator-initiated studies. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.jcvp.org). Reprints: Piero Pollesello, Critical Care Proprietary Products Orion Pharma, PO Box 65, FIN-02101 Espoo, Finland (e-mail: [email protected]). This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Levosimendan Efficacy and SafetyJ Cardiovasc PharmacoläVolume 76, Number 1, July 2020 Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. www.jcvp.org |5 Levosimendan, as reported by Pollesello et al 13 in 1994, binds to calcium-saturated human cTnC “in a hydrophobic patch of the N-domain near the site where the B helix is located when the protein is in its apoform.”Figure 1 shows an original diagram from the 1994 paper proposing a molecular model of the drug–ligand complex. That interaction leads to a stabilization of the calciumbound conformation of the regulatory (or N) domain of cTnC, which in turn causes a change in the conformation of the ‘switch’region of cardiac troponin I (cTnI) and detachment of cTnI from actin filaments. 14 Removal of the inhibitory effects of cTnI facilitates the formation of actin–myosin cross-bridges and the disinhibition of actomyosin adenosine triphosphate (ATP) synthase, resulting in enhanced cardiac contractility. 12,13,15–18 These findings, confirming that the binding of levosimendan to TnC is linked to calcium sensitization, proved to be the first stage of what has since matured into a longlasting research trail. 19–22 The calcium-sensitizing action of levosimendan is manifested as a leftward shift in the curve describing the relation between contractile force and calcium concentration, achieved through a direct effect on cTnC. That augmentation of contractility is not associated with increases in calcium transients, intracellular calcium, or myocardial oxygen consumption and is not compromised by pretreatment with betablockers. It should also be noted that the interaction between levosimendan and cTnC was shown to be more intense at high, systolic ionic calcium levels than at low, diastolic calcium levels, thus avoiding impairment of myocardial relaxation upon levosimendan administration. In addition to its principal action as a calcium-sensitizing agent, levosimendan was found in the course of its development program to mediate the opening of ATP-dependent potassium channels (K ATP channels) in vascular smooth muscle cells in various vascular beds. 23 By this mechanism of action, levosimendan induces an increase in blood perfusion in key organs and a systemic vasodilatation when levosimendan is used at doses within the recognized therapeutic range, which means that the drug must be considered and used as an inodilator and not simply as an inotrope. An essential aspect of the pharmacology and clinical profile of levosimendan is that its perfusion enhancement and systemic vasodilation effects are mediated through different mechanisms and may therefore be disentangled from each other. Levosimendan—acting on K ATP channels— has a different regional/peripheral versus systemic effect when compared with drugs such as the PDE inhibitors. 24 Separate emphasis must be placed on the discovery that levosimendan also opens the K ATP channels on the mitochondrial inner membrane. 25,26 This effect has been associated with cardioprotection, infarct size reduction, and mitigation of ischemia/reperfusion injuries in a range of in vitro, ex vivo, and in vivo studies in nonhuman species 27–31 andinclinical studies. 32 The aforementioned effects deriving from calcium sensitization and vasodilation are shared by the long-acting levosimendan metabolite OR-1896, whichisformedintheintestine through a reduction–acetylation pathway. 33–35 Free plasma concentrations of the parent drug and the metabolite are similar, but clinically meaningful plasma concentrations of pharmacologically active OR-1896 are detectable for days after an infusion of levosimendan and contribute to the persistence of the therapeutic effect after administration of the parent drug is stopped. 36 Beyond these primary mechanisms, levosimendan has been identified as having a range of ancillary actions (often described as pleiotropic effects) that do not involve an enhancement of cardiac function but which may be implicated in some of the clinical effects of and responses to levosimendan. 37 These include anti-inflammatory, antioxidative, and antiapoptotic actions that may be exerted in noncardiac organs, including the kidneys, liver, gut and splanchnic vasculature, lungs, and/or respiratory muscles (Fig. 2). Levosimendan inhibits only one isoform of intracellular PDE enzymes (PDE-III) and in a highly selective manner. Of note, the PDE-III over PDE-IV isoform selectivity of levosimendan is the highest known to date, with a ratio of 10,000, FIGURE 1. Early molecular model of the levosimendan–cTnC complex: The dihydropyridazinone ring of levosimendan is enclosed within a hydrophobic cleft formed by the amino acid residues Phe 20 , Ala 22 , Ala 23 , Phe 24 , Val 28 , and Phe 77 , and the phenyl ring of levosimendan is aligned to Met 81 , Cys 84 , and Met 85 . Source: Pollesello et al 13 Reproduced with permission from the American Society for Biochemistry and Molecular Biology. cTnC = cardiac troponin C. Papp et al J Cardiovasc PharmacoläVolume 76, Number 1, July 2020 6|www.jcvp.org Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. compared with 14 for milrinone. 38,39 It was proposed that inhibition of only the PDE-III isoform, not that of PDE-IV, would be insufficient to increase intracellular levels of cyclic adenosine monophosphate (cAMP) to the same levels as by simultaneous inhibition of the 2 isozymes. 38 This lack of PDE dependence further differentiates levosimendan from nonselective PDE inhibitors, such as milrinone, and provides an explanation of their different pharmacological behaviors, as in the case of the oxygen consumption to force production ratios. 38,40–42 However, this interpretation is not unanimous. Maack et al 43 have proposed that PDE-III inhibition by levosimendan may indeed play a relevant role in the pharmacological effects of levosimendan. In that interpretation, PDE-III inhibition by levosimendan synergizes with Ca 2+ sensitization for the resulting inotropic action. Interestingly, from this synergy, the authors predict that the more beta-adrenergic receptors are preactivated by endogenous or exogenous catecholamines, the more pronounced will be the inotropic effect of levosimendan, and the more this effect would be mediated by PDE-III inhibition rather than by Ca 2+ sensitization. Conversely, at low preactivation of beta-adrenergic receptors (such as during pharmacological beta-blockade), the Ca 2+ -sensitization effect of levosimendan would become more important for inotropy. The take-home message of a consensus paper from the Translational Working Group of the Heart Failure Association of the European Society of Cardiology (ESC) is that long-term use of drugs that exclusively target adrenergic signaling (eg, catecholamines and PDE inhibitors) is associated with adverse outcomes, whereas levosimendan, with its hybrid calcium sensitization and PDE-III inhibition properties, should be given the benefit of the doubt and further attention. The effect of levosimendan has also been studied in the presence of beta-blockers and/or inopressors. Xanthos et al 44 reported that the combination of epinephrine, atenolol, and levosimendan, when given during cardiac arrest and resuscitation in a pig model, resulted in improved 48-hour survival and postresuscitation cardiac function. Concurrently, Lochner et al 45 reported that the effects of levosimendan were not blunted by the presence of beta-blockers, as in the case of adrenergic inotropes. Levosimendan entered formal clinical evaluation and development in acute HF (AHF) in the mid-1990s. 46–48 Initially, it was established that IV levosimendan produced dose-dependent increases in cardiac output (CO) and decreases in pulmonary capillary wedge pressure (PCWP; Fig. 3). Those effects were not accompanied by significant increases in myocardial energy consumption, thus confirming the paradigm envisioned on the basis of the preclinical data. 28,49–51 FROM BENCH TO BEDSIDE Levosimendan entered clinical trials profiled as a novel inotrope with potential for the short-term treatment of acutely decompensated chronic HF. The regulatory studies program devised to evaluate it in this indication enrolled almost 4000 patients (Table 1) and produced the following key insights. Clinical Effects Hemodynamic Effects The hemodynamic effects of levosimendan seen in preclinical studies were confirmed. In patients with AHF, levosimendan achieves significant dose-dependent increases FIGURE 2. Mode of actions and pharmacologic effects of levosimendan: The mechanisms of action in the blue boxes contribute to the cardiovascular effects of the drug. Dotted lines mark pathways that are still not fully elucidated. EC 50 , half maximal effective concentration; K ATP , adenosine triphosphate–dependent potassium channels; PDE III, IV, phosphodiesterase isoforms in cardiac tissue. Adapted from: Al-Chalabi et al 216 Used with permission from Wolters Kluwer Health. Levosimendan Efficacy and SafetyJ Cardiovasc PharmacoläVolume 76, Number 1, July 2020 Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. www.jcvp.org |7 in CO and stroke volume and decreases in PCWP, mean blood pressure, mean pulmonary artery pressure, mean right atrial pressure, and total peripheral resistance. 52 In line with preclinical data, clinical studies have confirmed that levosimendan does not have a negative effect on diastolic function. In contrast, levosimendan has lusitropic FIGURE 3. Change in CO and PCWP: Change from baseline at the conclusion of a 24-hour infusion of levosimendan (given as a 10-minute bolus of 6–24 mg/kg, then an infusion of 0.05– 0.6 mg/kg/min), placebo, or dobutamine (6 mg/kg/min) in patients with stable HF. DOB, dobutamine; PBO, placebo. Data from: Nieminen et al. 52 TABLE 1. Regulatory Clinical Trials of Levosimendan Study n (Total/ LS) Dose (mg/kg/min)/Duration of LS Infusion Comparator Diagnosis/NYHA Class Primary Endpoint Dose ranging 52 151/95 0.05–0.6 24 h Placebo/ dobutamine CHF/III Invasive hemodynamics Dose escalation and withdrawal 64 146/98 0.1–0.4 24 or 48 h Placebo CHF/III–IV Invasive hemodynamics LIDO 63 203/103 0.1–0.2 24 h Dobutamine CHF/III–IV Invasive hemodynamics RUSSLAN 65 504/402 0.1–0.4 6h Placebo Post-AMI/IV Safety REVIVE I 62 100/51 0.1–0.2 24 h Placebo CHF/IV Clinical composite REVIVE II 62 600/299 0.1–0.2 24 h Placebo CHF/IV Clinical composite SURVIVE 61 1327/664 0.1–0.2 24 h Dobutamine CHF/IV Mortality AMI, acute MI; CHF, congestive heart failure; LS, levosimendan; NYHA, New York Heart Association. Papp et al J Cardiovasc PharmacoläVolume 76, Number 1, July 2020 8|www.jcvp.org Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. effects. 53,54 Inodilation is not only seen in the left side of the heart; right ventricular contractility is also improved, and pulmonary vascular resistance is decreased. 55–57 Pharmacokinetics in Clinical Trials As anticipated in nonclinical studies, in humans the hemodynamic effects of a 24-hour infusion of levosimendan are protracted for several days in patients with AHF due to of the presence of an active metabolite (Fig. 4A). 58–60 Effects on Neurohormones Rapid and sustained reductions in levels of natriuretic peptides were characteristic of levosimendan in its regulatory clinical trials. 61–63 The effect on natriuretic peptides closely follows the hemodynamic effects: both are evident for at least 1 week after the levosimendan infusion period (Fig. 4B). 58 In the trial Survival of Patients with Acute Heart Failure in Need of IV Inotropic Support (SURVIVE), in patients with acute decompensated HF, changes in brain natriuretic peptide (BNP) levels up to 5 days after the start of infusion of levosimendan could be seen, which was not the case after 48 hours of treatment with dobutamine. 61 Impact on Signs and Symptoms in AHF Levosimendan induces a rapid and sustained improvement in symptoms, as evidenced by Packer et al 62 and Slawsky et al. 64 In the second of those studies, relief of dyspnea was reported in 29% of levosimendan-treated patients compared with 15% of the placebo-treated patients 6 hours after starting the infusion (P= 0.037). 64 Improvement in symptoms was evident for up to 5 days. 62 Data on the use of rescue medications in the Randomised Evaluation of IV FIGURE 4. Pharmacokinetics of levosimendan: A, Differences in the area under the receiver operating characteristics curve (AUC) for changes in Doppler echocardiography–derived PCWP and CO in patients with acute HF treated with levosimendan or placebo (n = 11 in both groups) for 24 hours. Due to of the formation of the active metabolite, the hemodynamic effects are maintained several days after stopping levosimendan infusion. B, Median change in N-terminal prohormone atrial natriuretic peptide (NT-proANP) over 14 days in patients with HF receiving levosimendan or placebo (n = 11 in both groups) for 24 hours. Source: Lilleberg et al 58 Reproduced with permission from John Wiley and Sons. Levosimendan Efficacy and SafetyJ Cardiovasc PharmacoläVolume 76, Number 1, July 2020 Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. www.jcvp.org |9 Levosimendan Efficacy (REVIVE) program further confirm the effectiveness of levosimendan for symptom relief (Table 2). 62 Dyspnea and fatigue symptoms also responded better to levosimendan than to dobutamine in the Levosimendan Infusion versus Dobutamine (LIDO) trial, although not to the level required for statistical significance. 63 Clinical Outcomes Hospitalizations Patients treated with levosimendan in the LIDO study spent significantly more days alive and out of hospital than dobutamine-treated patients in a retrospective 180-day follow-up analysis (median 157 vs. 133 days; P= 0.027). 63 In the Randomised Study on Safety and Effectiveness of Levosimendan in Patients with Left Ventricular Failure After an Acute Myocardial Infarction (RUSSLAN), the combined risk of death and worsening HF was significantly lower in patients treated with levosimendan than in the control group during the infusion period (2% vs. 6%; P= 0.033) and at 24 hours (4% vs. 9%; P= 0.044). 65 In the REVIVE II study, a greater percentage of patients treated with levosimendan than placebo were released within 5 days (46% vs. 37%), and the mean duration of the initial hospitalization was almost 2 days shorter (7.0 vs. 8.9 days). 62 No significant intergroup difference was recorded in the SURVIVE trial (P = 0.3). 61 Mortality Thirty-one-day mortality in the LIDO trial indicated a survival advantage from levosimendan (mortality rate 8%, vs. 17% with dobutamine, HR 0.43, P= 0.049). 63 This was corroborated in a retrospective extension of follow-up to 180 days (mortality rate 26%, vs. 38% with dobutamine, HR 0.57, P= 0.029). In RUSSLAN, a survival benefit from levosimendan persisted at 180-day follow-up (23% vs. 31%; P= 0.053). 65 In the REVIVE and SURVIVE trials there were no significant differences in 3and 6-month overall survival between the study groups. 61,62 However, there was evidence of a survival gain from levosimendan treatment in SURVIVE patients who had a history of chronic decompensated HF or who were using beta-blockers. 66 In patients with existing chronic HF (88% of the study population), mortality was lower in the levosimendan group than in the dobutamine group at day 5 [3.4% vs. 5.8%, HR 0.58, 95% confidence interval (CI) (0.33–1.01), P= 0.05] and at day 14 [7.0% vs. 10.3%, HR 0.67, 95% CI (0.45–0.99), P= 0.045]. In patients who used beta-blockers (50% of the study population), mortality was significantly lower for levosimendan than for dobutamine at day 5 [1.5% vs. 5.1%, HR 0.29, 95% CI (0.11– 0.78), P= 0.01]. Safety A safety summary prepared by Orion Pharma in its capacity as sponsor of the regulatory studies found no difference in the proportion of patients with reduction in arterial blood pressure in response to treatment (23.1% vs. 23.1%), although REVIVE II, considered as a single study, diverged from this overall trend by showing more hypotension in the levosimendan arm. 62 In 2012, Landoni et al 67 collected data from 5480 patients in 45 randomized clinical trials and also carried out meta-analysis of the adverse events. No signals were seen for MI [data from 25 studies, RR 0.789, 95% CI (0.522–1.185), P= 0.3], ventricular arrhythmias [data from 9 studies, RR 0.885, 95% CI (0.611–1.281), P= 0.5], or supraventricular arrhythmias [data from 19 studies, RR 1.005, 95% CI (0.782–1.291), P= 0.9], but a numerical trend was seen for hypotension [data from 22 studies, RR 1.389, 95% CI (0.996–1.936), P= 0.53]. There are some contradictory or indirect and inconclusive reports related to the impact of levosimendan on platelet function, but a recent metaanalysis of 9 randomized controlled trials (RCTs) found that levosimendan did not increase postoperative bleeding risk. 68,69 Moreover, in Supplemental Digital Content 1 (see Supplementary Appendix, http://links.lww.com/JCVP/ A472) of the large regulatory trial Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) no signs of increase in periprocedural or postprocedural hemorrhage were seen after treatment with levosimendan. 70 Conversely, a later, independent meta-analysis of data from more than 5000 patients indicated increased risks of extrasystoles [RR 1.88, 95% CI (1.26–2.81)], hypotension [RR 1.33, 95% CI (1.15–1.53)], and headache or migraine [RR 1.94, 95% CI (1.54–2.43)] when compared with reference therapies. 71 Retrospective analyses of the REVIVE II data set identified low TABLE 2. Use of Rescue Medications in the REVIVE Program REVIVE I 62 REVIVE II 62 Levosimendan (n = 51) Placebo (n = 49) Levosimendan (n = 299) Placebo (n = 301) Rescue therapy (%) 16 29 15 26 Worsening dyspnea or tachypnea (%) 10 12 7 13 Increased pulmonary edema (%) 0 2 3 6 Diaphoresis (%) 0 2 1 1 Cool extremities and cyanosis (%) 2 2 0 2 Worsening renal function (%) 6 2 3 5 Decreased mental status (%) 0 0 1 2 Persistent/unresponsive symptoms (%) 10 18 6 11 Papp et al J Cardiovasc PharmacoläVolume 76, Number 1, July 2020 10 |www.jcvp.org Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. blood pressure at baseline as a possible risk factor for the use of levosimendan, and the current, approved Summary of Product Characteristics reflects that finding. 72 Dosing Levosimendan is given as a continuous infusion of 0.05 or 0.1 or 0.2 mg/kg/min for 24 hours, which may be preceded by a loading dose (bolus) of 6–12 mg/kg in 10 minutes. The loading dose was used in the active-controlled regulatory studies LIDO and SURVIVE, in which dobutamine served as comparator. Given that the elimination half-life of dobutamine is a few minutes while that of levosimendan is approximately 1 hour, the hemodynamic effects of dobutamine are seen almost immediately after the infusion is started, whereas a bolus of levosimendan is needed to see immediate effects. For consistency, all other studies in the regulatory clinical program were designed to include a bolus dose, followed by a maintenance infusion. It was later found that, in the case of hypovolemia or initial low blood pressure, a levosimendan bolus could be associated with hypotension or arrhythmias. Therefore, use of an initial bolus of levosimendan is now generally not recommended, and it has often been avoided in clinical practice and used only if an instant effect is sought and the systolic blood pressure is adequate. 73,74 Into Regular Clinical Use The experience gained in regulatory studies provided the basis for the first approval of IV levosimendan, which was introduced in Sweden in 2000 for the management of AHF with the name SIMDAX. Since then, more than 60 jurisdictions have approved the drug, including most of the countries of the EU and Latin America. Levosimendan is currently in active clinical evaluation in the United States. In the 20 years since its first introduction, IV levosimendan has been one of the notably few successful drugs entering the market in an underserved area of cardiovascular medicine: attempts at drug innovation in AHF have been characterized by repeated disappointments (either partial or total) or contradictory findings that have hindered progress. 75 Levosimendan itself has not been immune to some of the frustrations of research in this area: in particular, the nonunivocal findings on 6-month mortality in its regulatory studies complicated the process of establishing its therapeutic niche. Innovation in this area may have been poorly served by a regulatory emphasis on longer-term survival effects. This was perhaps misaligned with clinical realities and led to an emphasis on large trials which, by aggregating data from patients with different underlying pathophysiologies plus variations in both pharmacological and nonpharmacological treatments, may have generated signal-to-noise ratios that precluded the identification of a meaningful effect on the central end point of all-cause mortality/survival. The unsuitability of all-cause long-term mortality as an index of therapeutic effect was acknowledged by experts in the field of HF about a decade ago, but that realization came too late to influence the conduct of the regulatory trials of levosimendan. 76,77 These obstacles notwithstanding, pooled analysis of the outcomes of the levosimendan regulatory trials provided strong indications, albeit not always statistically conclusive proof, of an overall survival benefit (Fig. 5). Extensive experience with levosimendan has been accrued in smaller, often single-center, nonregulatory studies. Many of those studies indicate a survival benefit from levosimendan, a finding affirmed in meta-analysis. 67 Levosimendan has been evaluated in more than 200 clinical trials during its lifetime, in an extensive range of therapeutic settings. Experience in all those areas has been evaluated in meta-analyses, 31 of which have been conducted in the past 3 years (Fig. 6). In every instance, levosimendan FIGURE 5. Effect of levosimendan on survival in the regulatory clinical trials: Meta-analysis of the clinical trials considered by regulatory authorities for the introduction of levosimendan. *Pooled statistic calculated using the Cochran–Mantel– Haenszel test, controlling for study. Source: Pollesello et al. 80 Reproduced with permission from Elsevier. Levosimendan Efficacy and SafetyJ Cardiovasc PharmacoläVolume 76, Number 1, July 2020 Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. www.jcvp.org |11 was associated with a favorable impact on the outcomes under consideration but, depending on the data selected, statistical significance in some cases remained elusive. Key therapeutic areas analyzed in this way have included AHF, advanced HF (AdHF), cardiac surgery, and sepsis, all of which have provided indications of benefit from levosimendan therapy. The broadly affirmative findings of these exercises may be compared with similar appraisals of dobutamine and PDE inhibitors, which have been associated with overall worse mid-to-long-term prognosis. 78–80 These contrasting findings highlight the distinction between inotropes that act, via either adrenergic or PDE-targeted pathways, to increase intracellular cAMP levels in cardiomyocytes and levosimendan, realizing the ambitions of its inventors by promoting cardiac contractility without compromising the longer-term viability of cardiac muscle cells. This distinction is also illuminated by findings from the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF) registry, data from which were strongly indicative of survival benefit from levosimendan vis-à-vis adrenergic/calcium-mobilizing inotropes, such as dobutamine. 81 LEVOSIMENDAN IN CURRENT USE The nonunivocal findings of long-term survival benefit from short-term treatment with IV levosimendan have not prevented the drug from establishing itself in the therapeutic repertoire: it has been used in almost 2 million patients since 2000, when its first market authorization was granted by the Swedish regulatory authorities on the basis of the data available at that time. Its favorable, rapid, and sustained impact on hemodynamics, neurohormone levels, and symptoms in acute decompensated HF are undisputed and of clear therapeutic value. Formal acknowledgement of that value emerged in 2005, when it was mandated in the ESC guidelines. 82 In the subsequent European guidelines (2008, 2012), the endorsements of levosimendan were more cautious, reflecting a general dissatisfaction of the HF medical community with the concept of inotropy. 83,84 Levosimendan is currently recommended in the acute treatment of HF to reverse the effect of beta-blockade, if beta-blockade is thought to be contributing to hypotension with subsequent hypoperfusion. 85 Due to the large therapeutic field they encompass, the European guidelines on acute and chronic HF are not as detailed as they could be and, in recommending therapeutic agents, ignore some of the different etiologies and manifestations of AHF. Supplemental Digital Content 1 (see Supplementary Information, http://links.lww.com/JCVP/ A472) and recommendations can be found in more than 20 expert consensus papers coauthored by more than 180 clinicians from 30 countries who have discussed when and how to use levosimendan in different therapeutic settings, including AHF and cardiogenic shock, 74,81,86–88 AdHF, 89–92 perioperative use, 93–95 and use in the intensive care unit (ICU), 96 and who have described its cardiorenal effects, 88,97 its effects on quality of life, 98,99 exercise performance, 100 lung function, 101 and pharmacoeconomic considerations. 102 In the context of a 20-year retrospective, it is worth noting at this point that its complex mode of action might have had the potential to disadvantage levosimendan both in fact and in perception. In fact, that plurality of effects has emerged as both an important aspect of the drug’s clinical versatility and usefulness and as a stimulant to informed speculation among experts and to medical research. 73,92,94,96,103 Levosimendan in Acute Settings The most recent ESC guidelines, issued in 2016, identify short-term treatment with IV levosimendan (along with adrenergic inotropes or PDE inhibitors) as an option in the acute-phase management of “patients with hypotension (SBP ,90 mmHg) and/or symptoms of hypoperfusion despite adequate filling status, to increase CO, increase blood pressure, improve peripheral perfusion and maintain endorgan function.” 85 The ESC statement further endorses the short-term use of levosimendan to circumvent the effects of beta-blockade “if beta-blockade is thought to be contributing to hypotension with subsequent hypoperfusion.”The high proportion of patients now receiving beta-blockers as part of the treatment repertoire for chronic HF means that levosimendan has become an important resource in the management of acute decompensations in those patients. The vasodilator dimension of levosimendan’s pharmacology is pertinent to the drug’s use in low-output states such as AHF, in which a key pathology is organ hypoperfusion. A drug that both augments CO and improves vasodilatation may FIGURE 6. Results of 64 meta-analyses of levosimendan clinical trials. Refer to the supplementary material for details of the individual meta-analyses. Papp et al J Cardiovasc PharmacoläVolume 76, Number 1, July 2020 12 |www.jcvp.org Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. 58. Lilleberg J, Laine M, Palkama T, et al. Duration of the haemodynamic action of a 24-h infusion of levosimendan in patients with congestive heart failure. Eur J Heart Fail. 2007;9:75–82. 59. Kivikko M, Lehtonen L, Colucci WS. Sustained hemodynamic effects of intravenous levosimendan. Circulation. 2003;107:81–86. 60. Antila S, Kivikko M, Lehtonen L, et al. 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