The role of Ca ++ -sensitizers for the treatment of heart failure Andreas Lehmann, a Joachim Boldt, a and Jürgen Kirchner b

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1 The role of Ca ++ -sensitizers for the treatment of heart failure Andreas Lehmann, a Joachim Boldt, a and Jürgen Kirchner b For increasing myocardial contractility in patients with cardiac failure, catecholamines, phosphodiesterase-iii (PDE) inhibitors, and calcium sensitizers are available. Improving myocardial performance with catecholamines and PDE inhibitors leads to increased intracellular calcium concentration as an unavoidable side effect. An increase in intracellular calcium can induce harmful arrhythmias and increases the energetic demands of the myocardium. Long-term trials with PDE inhibitors have raised concerns about the safety of positive inotropic treatment for cardiac failure. Calcium sensitizers are a new class of inotropic drugs. They improve myocardial performance by directly acting on contractile proteins without increasing intracellular calcium load. Thus, they avoid the undesired effects of an increased intracellular calcium load. Calcium sensitizers may enhance myocardial performance without increasing myocardial oxygen consumption and without provoking fatal arrhythmias. Two calcium sensitizers are available for the treatment of cardiac failure in men. Pimobendan is a drug with positive inotropic effects that additionally inhibits the production of proinflammatory cytokines. However, it exerts a significant inhibition of PDE at clinically relevant doses. Levosimendan is a calcium sensitizer with no major inhibition of PDE at clinically relevant doses. It opens ATP-dependent potassium channels and thus has vasodilating and cardioprotective effects. The most important studies of the long-term treatment of stable cardiac failure with pimobendan and on the short-term treatment of unstable cardiac failure with levosimendan are presented. Curr Opin Crit Care 2003, 9: Lippincott Williams & Wilkins, Inc. Mechanism of action Calcium sensitizers are a new class of positive inotropic drugs. Two drugs of this class are currently being marketed. Levosimendan has official approval for intravea Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, and b Orion Pharma GmbH, Hamburg, Germany Supported by a grant from Orion Pharma, Espoo, Finland. Correspondence to Dr. Andreas Lehmann, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D Ludwigshafen, Germany Dr.A.Lehmann@web.de Current Opinion in Critical Care Current Opinion in Critical Care 2003, 9: Abbreviations CO cardiac output LVEF left ventricular ejection fraction PDE phosphodiesterase-iii PCWP pulmonary capillary wedge pressure SVR systemic vascular resistance 2003 Lippincott Williams & Wilkins Introduction For acute worsening of heart failure, the short-term administration of levosimendan, a new inotrope with calcium sensitizing properties, appears to be safer than dobutamine. Also, in acute heart failure after myocardial infarction, levosimendan improved symptoms and halved mortality during first 72h, a difference in mortality which was maintained over the next 6 months. However, this effect on mortality requires further confirmation in formal trials. This paragraph was recently published in Guidelines for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology [1]. For the first time, a positive inotropic drug seems to have beneficial effects on long-term survival in patients with acute decompensated heart failure [2,3 ]. For all other currently available positive inotropic drugs, although they are commonly used in critical care medicine, no evidence-based data exist on improving the outcome [1,4]. However, using catecholamines and phosphodiesterase- III (PDE) inhibitors for the treatment of symptomatic heart failure may even lead to treatment-related complications. It has been shown (level of evidence: A) (Table 1) that the prolonged oral application of PDE inhibitors increases mortality [1,5,6]. Data on the long-term intermittent intravenous infusion of a positive inotropic drug for symptomatic and refractory end-stage heart failure demonstrate that this treatment is not useful and can even be harmful in some patients (level of evidence: C) (Table 1) [4,7]. The major concern is whether positive inotropy can be achieved without harmful side effects. The current available positive inotropic drugs, catecholamines and PDE inhibitors, cause an increase of intracellular calcium in the cardiac myocytes [8]. The increase of intracellular calcium leads to calcium-induced arrhythmias and increases the metabolic demands of the myocytes [9]. The solution of the problem would be drugs directly interacting with the contractile proteins and thus increasing contractility without increasing intracellular calcium. This is the concept of calcium sensitization as proposed by Ruegg [10]. 337

2 338 Cardiovascular system Table 1. Level of evidence proposed by the European Society of Cardiology Level of evidence A B C Available evidence 1 Randomized clinical trial 1 Randomized clinical trial Expert consensus based on trials and clinical experience Therapeutic recommendations of the Guidelines of the European Society of Cardiology [1 ] and of the American College of Cardiology/American Heart Association [4 ] are based on the degree of available evidence from which data were derived. nous application in several countries of the European Union, like Austria, Finland, Greece, Iceland, Spain, and Sweden and several countries of South America [11]. For use in men, pimobendan is approved in Japan only. Pimobendan is approved in several Western European countries for the treatment of cardiac failure in dogs [12]. This article attempts to give an update on calciumsensitizing drugs. It will be focused on the two calcium sensitizers clinically available, levosimendan and pimobendan, for the treatment of patients with cardiac failure. Myocardial contraction is based on the interaction of actin and myosin during systole. During diastole, crossbridging of actin and myosin is blocked by troponintropomyosin complex. By increasing intracellular calcium during systole, calcium binds to troponin C, resulting in a conformational change of troponin-tropomyosin complex. This allows cross-bridging of actin and myosin; contraction starts [13]. The concept of calcium sensitization hypothesizes that myocardial contractility is increased by drugs directly interacting with contractile proteins [9,10]. Figure 1 demonstrates the molecular mechanisms of action and energetic demands of levosimendan in comparison with catecholamines and PDE inhibitors. Haikkala and Pollesello [9] distinguish three possible mechanisms of action for the calcium sensitizers: 1. increased affinity of ctnc for calcium 2. direct stabilization on the calcium-induced conformation of ctnc 3. action on other target proteins in the molecular cascade of myocardial contraction The first mechanism, the increased affinity of calcium to ctnc, is proportionally more efficient at low calcium concentrations. Low intracellular calcium concentrations are found during relaxation, ie, diastole. Therefore, drugs acting by this mechanism prolong relaxation and may significantly impair diastolic cardiac function [9]. Pimobendan belongs to this subgroup of calcium sensitizers and has been shown to prolong relaxation in cardiac muscle strips [14]. Pimobendan exerts a significant inhibition of PDE at doses increasing myocardial contractility [15 17]. Pimobendan inhibits the production of proinflammatory cytokines, such as the transcription factor NF- B and nitric oxide [17,18]. Thus, it is proposed to have beneficial effects in viral myocarditis that are partially mediated by the unique inhibition of proinflammatory cytokine production and nitric oxide synthesis [18]. The second mechanism tries to avoid the undesired effects of calcium sensitization on cardiac relaxation during diastole. These drugs stabilize the calcium-induced conformational change of ctnc only during systole by binding only to the calcium-bound conformation of ctnc [9,19,20]. This leads to a calcium-dependent binding of the drug to ctnc without increasing the affinity of calcium to ctnc. This results in minimal effects on diastole [9]. Levosimendan belongs to this group of drugs. Besides increasing contractility by acting in a calcium dependent manner on ctnc, levosimendan has been found to be an opener of ATP-sensitive potassium channels (K ATP channels) in vascular smooth muscle cells, cardiac myocytes, and mitochondria [21 23]. In vitro levosimendan is a highly selective inhibitor of PDE; however, at concentrations exceeding the pharmacologically relevant concentrations for inducing positive inotropic effects [24]. The positive inotropic effects of levosimendan are not antagonized by inhibition of the campdependent protein kinase, in contrast to the PDE inhibitors [25]. Thus, levosimendan exerts positive inotropic effects by stabilizing the calcium-induced conformational change of ctnc, resulting in a prolonged crossbridging time of actin and myosin (Figure 1) [9,19,20]. In addition, levosimendan has vasodilating effects and antiischemic effects by opening K ATP channels [21,26,27,28]. Drugs acting by the third mechanism target a protein beyond ctnc in the cascade of myocardial contraction. All the drugs belonging to this group, however, have been found to prolong cardiac relaxation [9,29,30]. This mechanism is not directly affected by calcium and is thus equally powerful during the whole contraction-relaxation cycle, ie, systole and diastole [9]. No drug of this type is clinically available. Table 2. Change in hemodynamics with levosimendan in decompensated cardiac failure Levosimendan Placebo CI (L/min/m 2 ) +0.7 ± ± 0.1 HR (min 1 ) +6±1 +1±1 MAP (mmhg) 4 ± 1 +1 ± 1 PCWP (mmhg) 6 ± 1 0 ± 1 SVR (dyne s cm 5 ) 514±50 +41±72 PVR (dyne s cm 5 ) 80±13 +33±19 Change in hemodynamics from baseline values 6 hours after randomization. An increase from baseline is indicated by +, a decrease from baseline by. CI, cardiac index; HR, heart rate; MAP, mean arterial pressure; PCWP, pulmonary capillary wedge pressure; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance. Published with permission [37].

3 Cardiac failure and calcium sensitizers Lehmann et al. 339 Figure 1. Mechanism of action of positive inotropic drugs and energetic demands, demonstrating the molecular mechanism of myocardial contraction Myocardial contraction is based on the interaction of actin and myosin during systole. During diastole, cross-bridging of actin and myosin is blocked by troponin tropomyosin-complex. By increasing intracellular calcium during systole, calcium binds to troponin C, resulting in a conformational change of troponin-complex. This change allows a cross-bridging of actin and myosin; contraction starts. The energetic demand for one cross bridge of actin and myosin is one molecule of ATP. Above, the untreated situation in the myocardium is shown resulting in a normal cross-bridging time of actin and myosin and normal energy consumption. Center, levosimendan stabilizes the calcium-induced conformational change of troponin C during systole, resulting in an increase of cross-bridging time. The increased cross-bridging time increases contractility. The number of cross bridges is not increased. The energetic demands remain unchanged by levosimendan. Intracellular calcium load is not augmented. Below, catecholamines and phosphodiesterase-iii inhibitors raise intracellular calcium concentration during systole, resulting in an increased number of cross-bridges during systole. The increased number of cross bridges results in increased contractility. The energetic demands are increased by the additional number of cross bridges and by the increased work of calcium pumps and the end of systole. chronic heart failure For treatment of chronic heart failure, both clinically available calcium-sensitizers, pimobendan and levosimendan, were tested. Two different doses of pimobendan (2.5 mg and 5 mg) were tested in 317 patients (left ventricular ejection fraction [LVEF] <45%) with chronic heart failure [31 ]. Primary endpoint was exercise capacity. Both doses improved exercise duration by 6% (P < 0.05) but had no effect on oxygen consumption and quality of life (assessed by questionnaire). Even though no proarrhythmic effects of pimobendan were seen on 24- hour electrocardiogram, the risk of death was 1.8 times higher in both pimobendan groups than in the placebo group. These negative effects on the risk of death might have been explained by the PDE inhibitor effects of pimobendan [14,15]. Pimobendan was tested versus placebo in 306 patients with stable chronic heart failure (New York Heart Association [NYHA] II to III, LVEF <45%) for as long as 52 weeks [32 ]. Death and hospitalization occurred in 10.1% percent of the pimobendan patients versus 15.3% in the placebo group (not significant). However, the in-

4 340 Cardiovascular system cidence of adverse cardiac events was 45% lower in the pimobendan group (P = 0.035). The authors concluded that long-term treatment with pimobendan in patients with stable chronic heart failure lowered morbidity, improved physical activity, and did not increase mortality [32 ]. Smaller studies and casuistic reports on the beneficial effects of pimobendan in patients with cor pulmonale, dilated cardiomyopathy and chronic obstructive pulmonary disease, and moderate nonischemic heart failure were published in Japan [33 35]. Levosimendan was investigated in a dose finding study [36] including 151 patients with stable heart failure (NYHA III) of ischemic origin. Levosimendan (bolus 3 to 36 µg/kg, continuous infusion 0.05 to 0.6 µg/kg/min for 24 hours) was tested versus placebo and dobutamine (6 µg/kg/min). The desired hemodynamic improvements were seen in 14% of the patients receiving placebo, in 70% of the patients receiving dobutamine, and in 50% (lowest dose) to 88% (highest dose) of the patients receiving levosimendan. Side effects like headache, nausea, and hypotension were seen at higher doses of levosimendan. The authors concluded that dosing levosimendan with a 10-minute bolus of 6 to 24 µg/kg followed by a continuous infusion of 0.05 to 0.2 µg/kg/min was well tolerated and led to favorable hemodynamic effects [36]. decompensated cardiac failure For the treatment of acute deterioration of cardiac failure, only data on levosimendan were published. Levosimendan was compared with placebo in a series of 146 patients admitted to the hospital for management of acute decompensated heart failure (LVEF <25%, CI <2.0 L/min/m 2 ) [37]. The patients were randomized 2:1 to receive either levosimendan (bolus 6 µg/kg, continuous infusion 0.1 µg/kg/min) or placebo. At hourly intervals, levosimendan was uptitrated (repeat bolus 6 µg/kg, continuous infusion 0.1 µg/kg/min) until a maximum rate of 0.4 µg/kg/min was achieved or a doselimiting event occurred. At 6 hours, the mean infusion rate of levosimendan was 0.26 ± 0.08 µg/kg/min. The hemodynamic data are shown in table 3. Adverse events were reported in 17% of the patients in the levosimendan group and 19% of those in the placebo group. The authors concluded that levosimendan caused a rapid dose-dependent improvement of hemodynamics in patients with decompensated heart failure. The hemodynamic profile of levosimendan was best described by a positive inotropic drug with vasodilating properties [37]. In the levosimendan infusion versus dobutamine (LIDO) study, levosimendan was tested in 203 patients admitted to the hospital with low-output cardiac failure [2 ]. LVEF was <35%, cardiac index (CI) was <2.5L/ min/m 2, and pulmonary capillary wedge pressure (PCWP) was greater than 15 mm Hg, as assessed by invasive hemodynamic monitoring. Patients from different categories were included to the study: acute deterioration of heart failure (including patients awaiting cardiac transplantation), acute heart failure, or severe heart failure after cardiac surgery. In both groups, approximately 90% of the patients belonged to the first group, ie, deterioration of chronic heart failure despite optimal treatment with oral vasodilators and diuretics. The primary endpoint of this study was hemodynamic improvement (increase in cardiac output [CO] >35% and decrease in PCWP >25% 24 hours after randomization). One hundred patients received dobutamine (5 µg/kg/min continuous infusion), and 103 patients were treated with levosimendan (24 µg/kg bolus, 0.1 µg/kg/min continuous infusion). In both groups, the infusion rate was doubled if 2 hours after randomization the desired hemodynamic effects (CO >35% and PCWP <25%) were not seen. Significantly (P < 0.05) more patients in the levosimendan group (28%) achieved an hemodynamic improvement (CO >35% and PCWP <25%) than in the dobutamine group (15%) (Figure 2) [2 ]. Interestingly enough, a single infusion of levosimendan within 24 hours had beneficial effects on survival 31 days and 180 days after randomization (Figure 3, Table 3) [2 ]. The authors concluded that levosimendan could be a better choice than dobutamine as an inotropic agent in patients with decompensated heart failure [2 ]. An interesting pharmacoeconomic calculation was recently published on the basis of data from the LIDO study [38]. In comparison with dobutamine, in the levosimendan group the mean cost per patient increased by 1108 because of the costs of the study drug. A life-year saved by levosimendan costs approximately 3200 at the European level. The authors concluded that although the patients treated with levosimendan were alive for more days and thus were at risk for longer hospitalization, there was no increase in hospitalization or hospitalization costs in the levosimendan group compared with the dobutamine group [38]. ischemic heart failure In the randomised study on safety and effectiveness of levosimendan in patients with left ventricular failure due to an acute myocardial infarct (RUSSLAN), the safety and effectiveness of levosimendan was tested in 504 patients [3 ]. Patients with evidence of left ventricular failure on chest radiograph and a clinical need for inotropic therapy based on symptoms despite optimal therapy with diuretics and vasodilators were included to the study within 5 days after acute myocardial infarction. Four different doses of levosimendan were compared with placebo in a double-blind manner (Table 4). Levosimendan was given for a total of 6 hours. The patients

5 Cardiac failure and calcium sensitizers Lehmann et al. 341 Figure 2. LIDO study: percentage change of hemodynamic parameters 24 hours after start of treatment LIDO Study, levosimendan infusion versus dobutamine; CI, cardiac index; PCWP, pulmonary capillary wedge pressure; SV, stroke volume; HR, heart rate; sbp, systolic blood pressure. Asterisk indicates P < Adapted with permission [2 ]. were not monitored by Swan-Ganz catheter. The primary endpoint of the study was hypotension or myocardial ischemia of clinical significance as judged by an independent safety committee. Of all the patients treated with levosimendan, 13.4% experienced ischemia and/or hypotension, compared with 10.8% of the patients in the placebo group. Only in patients receiving the highest dosage of levosimendan (bolus 24 µg/kg, continuous infusion 0.4 µg/kg/min) was a higher frequency of hypotension and/or ischemia seen in comparison with those receiving placebo [3 ]. The difference did not reach statistical significance. However, levosimendan-treated patients had a significant lower risk of death and worsening heart failure than did patients treated with placebo during both the 6-hour infusion period and over 24 hours. Mortality was lower in the levosimendan group compared with the placebo group 14 days after randomization (11.7% vs 19.6%, P = 0.033). This effect was maintained 180 days after inclusion in the study, but the difference did not reach statistical significance (levosimendan 22.6%; placebo 31.4%, P = 0.053) [3 ]. The authors concluded that a levosimendan dosage of 0.1 to 0.2 µg/kg/min was safe in patients with acute ischemic left ventricular failure complicating acute myocardial infarction [3 ]. In a small series, levosimendan was given to patients with cardiogenic shock by acute myocardial ischemia who were scheduled for emergent surgical revascularization [39]. The results were encouraging, thus proposing levosimendan as an inoprotector in patients with acute ischemia requiring inotropic support. heart failure in patients undergoing cardiac surgery In cardiac surgical patients with severe left ventricular dysfunction and low-output syndrome, nearly no data about the treatment with levosimendan have been published so far. In the LIDO study, only 2 to 4% of the included patients had postoperative cardiac failure [2 ]. In both groups levosimendan and dobutamine more than 95% of the patients did not undergo cardiac surgery [2 ]. Only small casuistic reports of levosimendan for the treatment of cardiogenic shock in patients with acute myocardial ischemia have been submitted for publication [39]. Although these results were favorable in patients with acute ischemia simultaneously requiring inotropic support, no evidence-based data for this specific indication exist, to the authors knowledge. In 23 patients with good left ventricular function undergoing cardiac surgery, two different dosages of levosimendan (8 µg/kg and 24 µg/kg) were compared with placebo [41 ]. Hemodynamics and myocardial substrate utilization were measured. Levosimendan increased CO and decreased systemic vascular resistance (SVR) and pulmonary vascular resistance. Coronary sinus blood flow was increased by levosimendan. The authors concluded that levosimendan did not increase myocardial oxygen consumption despite improved cardiac performance [40 ]. In 18 patients undergoing elective cardiac surgery, levosimendan (bolus 18 µg/kg and continuous infusion 0.2 µg/kg/min vs bolus 24 µg/kg and continuous infusion 0.3 µg/kg/min) was tested. Levosimendan increased CO and decreased SVR in a dose-dependent fashion, in comparison with placebo [41].

6 342 Cardiovascular system Figure 3. Kaplan-Meier estimates of risk of death during the first 180 days after start of treatment After 180 days. 27 (26%) patients in the levosimendan group died, and 38 (38%) patients in the dobutamine group died (P = 0.029). Adapted with permission [2 ]. septic heart failure In severe sepsis, the hemodynamic situation of a patient is characterized by a reduction in peripheral vascular tone in both arterial and venous sites, a defect in oxygen utilization, and myocardial dysfunction [42,43 ]. In septic myocardial depression, there is biventricular dilatation, decreased ejection fraction, and a decrease in the response to fluid load and positive inotropic stimulation [43 ]. Septic myocardial depression is reversible within 7 to 10 days in surviving patients [43 ]. Myocardial hypoperfusion is not responsible for septic cardiac dysfunction. A circulating factor or factors appear to have a significant role in this phenomenon. This factor seems to be represented by low concentrations of tumor necrosis factor- and interleukin-1- acting synergistically on the myocardium through a combination of nitric oxide dependent and independent alterations of myocardial Table 3. LIDO study: mortality after randomization Days after randomization Levosimendan Dobutamine P 31 8 (8%) 17 (17%) (26%) 38 (38%) Levosimendan infusion versus dobutamine (LIDO study): Number and percentage of patients dying within 31 days and 180 days after randomization based on the intention to treat analysis. Published with permission [2 ]. contractility. The sensitivity of cardiac myocytes to calcium is decreased in endotoxic shock in animals [45]. Despite major progress in understanding the mechanism of myocardial depression in sepsis, successful therapeutic approaches to improve the outcome in human trials have not yet been demonstrated. The primary aim in sepsis is to restore adequate organ perfusion and oxygen delivery by fluid resuscitation and vasopressor and/or inotropic support [45 48]. MCI-154, a calcium sensitizer, reversed the decreased sensitivity to calcium and increased contractility in myocardial muscle preparations from rats in endotoxic shock [45]. In a porcine model of endotoxemia, high-dosage levosimendan (bolus 200 µg/kg, continuous infusion 3.3 µg/kg/min) was tested [49]. Cardiac index and sys- Table 4. RUSSLAN study: doses of levosimendan in patients with heart failure after acute myocardial infarction Loading dose Continuous infusion N 6 µg/kg 0.1 µg/kg/min µg/kg 0.2 µg/kg/min µg/kg 0.2 µg/kg/min µg/kg 0.4 µg/kg/min 100 Placebo Placebo 102 Randomised study on safety and effectiveness of levosimendan in patients with left ventricular failure due to an acute myocardial infarct (RUSSLAN study). Published with permission [3 ].

7 Cardiac failure and calcium sensitizers Lehmann et al. 343 temic oxygen delivery were improved by levosimendan in endotoxemia. However, blood pressure and SVR were reduced by levosimendan during the initial phase of endotoxin shock. Splanchnic perfusion and oxygen delivery were improved by levosimendan. The authors concluded that levosimendan improved cardiac output and systemic and gut oxygen delivery. The vasodilatory properties of the drug were well tolerated in this porcine model of endotoxemia, as stated by the authors [49]. No data on using a calcium sensitizer in septic heart failure in humans have been published. Whether the vasodilatory effects of the calcium sensitizers play a favorable role in septic shock remains to be established. Conclusion Calcium sensitizers are a new class of inotropic drugs. They improve myocardial performance by directly acting on contractile proteins without increasing intracellular calcium load [9]. An increased intracellular calcium concentration is an unavoidable side effect of the inotropic treatment with catecholamines and PDE inhibitors [9]. An increase in intracellular calcium can induce harmful arrhythmias and increases the energetic demands of the myocardium. Pimobendan is a calcium sensitizer with significant PDE inhibition. The long-term application of pimobendan may increase mortality in patients with chronic heart failure (level of evidence: B) but seems to decrease cardiac morbidity (level of evidence: B) [31,32 ]. Levosimendan is a calcium sensitizer with no significant inhibition of PDE at clinically relevant doses. It has positive inotropic effects and activates K ATP -channels. Thus, levosimendan has cardioprotective effects at a dose enhancing myocardial contractility [27]. Short-term levosimendan appears to be safer than dobutamine for acute worsening of chronic heart failure (level of evidence: B) [2 ]. Its short-term application in patients with cardiac failure complicating myocardial infarction was shown to be safe (level of evidence: B) [3 ]. No evidence-based data for the use of calcium-sensitizers in patients with cardiac failure undergoing cardiac surgery and for cardiac failure due to septic shock exist. No data from humans exist for treatment with levosimendan for cardiac failure resulting from septic shock. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: Of special interest Of outstanding interest 1 Remme WJ, Swedberg K, and the Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology: Guidelines for the diagnosis and treatment of chronic heart failure. 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