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Simdax® Gives You Time When It's Needed Most1 EASE THE CHALLENGE OF TREATING THE FAILING HEART SIMDAX® GIVES YOU TIME WHEN IT’S NEEDED MOST1 Reference: 1. Nieminen MS et al. Eur Heart J Suppl. 2017;19(suppl_C);C15-C21. SIMDAX® GIVES WITH THREE YOU TIME WHEN PHARMACOLOGICAL IT’S NEEDED MOST1 EFFECTS… SIMDAX® is the only inodilator2,3 to provide The clinical effects of SIMDAX® are mediated through:1 The unique triple mechanism sustained hemodynamic benefits3–8 and symptom • Increased cardiac contractility by calcium sensitization of action of levosimendan1 3–5,9,10 control to patients with acute heart failure, of troponin C and in need of inotropic therapy. • Vasodilation through the opening of potassium channels in the vasculature smooth muscle • Cardioprotection, anti-ischemic antistunning effects Cardioprotection Mitochondrial through the opening of mitochondrial potassium K channel opening channels in cardiomyocytes ATP levosimendan References: 1. Nieminen MS et al. Eur Heart J Suppl. 2017;19(suppl C);C15-C21. 2. Papp Z et al. Int J Cardiol. 2012; 159:82–87. 3. Nieminen Inotropy Vasodilation MS et al. Heart Lung Vessel. 2013;5(4):227–245. 4. Follath et al. Lancet. Cardiac Smooth muscle 2002;360:196–202. 5. Slawsky et al. Circulation. 2000;102:2222–2227. 6. Troponin C KATP channel Nieminen et al. J Am Coll Cardiol. 2000;36:1903–1912. 7. Kivikko et al. sensitization activation Circulation. 2003;107:81–86. 8. Lilleberg et al. Eur J Heart Fail. 2007;9:75– 82. 9. Mebazaa et al. JAMA. 2007;297:1883–1891. 10. Packer et al. JACC Heart Fail. 2013;1(2):103–111. Reference: 1. Papp Z et al. Int J Cardiol. 2012;159:82–87. 3 …SIMDAX® PROVIDES MULTIPLE IMPROVING BENEFITS WITHIN AND BEYOND HEMODYNAMICS… THE HEART ® 2 Therapy with SIMDAX , the first-in- Levosimendan In patients with heart failure, the positive inotropic and Improvement in hemodynamic performance class among the cardio-protective vasodilatory actions of SIMDAX® result in an increased p=0.002 Levosimendan inodilators, brings multiple beneficial contractile force, and a reduction in both preload 30 Circulation Heart Dobutamine cardiovascular effects.1,2 and afterload.1,2 25 28% Opening of Opening of ++ Ca sensitivity of potassium channels potassium channels SIMDAX® increases cardiac output, stroke volume and 20 contractile proteins in smooth muscle in mitochondria ejection fraction, and reduces pulmonary capillary wedge Multiple action of 15 pressure, right atrial pressure, and peripheral vascular levosimendan in the 15% Vasodilation + Inotropy + Lusitropy 1,2 cardiovascular system1 resistance. 10 Patients achieving primary endpoint (%) 5 Improved LV n n n y performance 0 24 hours 24 hours Improved RV n=103 n=100 Reductio of ischemia/ reperfusio injury Protectio against myocardial stunning Peripher Kidney Gut Lung Coronary performance References: Proportion of patients with hemodynamic improvement after a 24-hour 1. Pinto BB et al. Curr Opin Anaesthesiol. 2008;21:168–177. References: 1. Nieminen MS et al. J Am Coll Cardiol. 2000;36:1903–1912. infusion, defined as a 30% or greater increase in cardiac output and a 25% or 2: Farmakis D et al. Int J Cardiol. 2016;222:303-12 2. Follath F et al. Lancet. 2002;360:196–202. greater decrease (at least 4 mmHg) in pulmonary capillary wedge pressure.2 4 5 …WITHOUT AN THE HEMODYNAMIC INCREASE IN OXYGEN BENEFITS OF SIMDAX® CONSUMPTION ARE SUSTAINED… The positive inotropic effects of SIMDAX® are achieved No significant increase in After operation, in a comparative study vs milrinone, Sustained effects of levosimendan 1,2 without an increase in oxygen consumption. oxygen consumption Levosimendan the positive hemodynamic effects of 19 hours when used in cardiac surgery Levosimendan Dobutamine treatment with SIMDAX® lasted much longer than Milrinone ) L/min those from 83 hours treatment with milrinone.1 mono 0.12 p=0.05 40 0.1 ) 2 0.08 n.s. 30 0.06 SVI (ml/m 0.04 20 0.02 Base Post End T0 T6 T12 T24 T48 CPB Surgery Myocardial consumption index (K 0 Stroke volume index (SVI) at the start of surgery (base), 15 min after the end Baseline Treatment (2 hr infusion) of cardiopulmonary bypass (CPB) (post-CPB), at the end of the operation (end References: surgery), at arrival in the intensive care unit (T0), and 6 (T6), 12 (T12), 24 (T24), 1. Nieminen MS et al. J Cardiovasc Pharmacol. 2009;53(4):302–310. A significant increase in the oxygen consumption is induced by dobutamine Reference: and 48 (T48) hours later in both groups. Data are mean±sd. Levosimendan 2. Ukkonen H et al. Clin Pharmacol Ther. 1997;61:596–607. while no difference is noticed during treatment with levosimendan.2 1. De Hert SG et al. Anesth Analg. 2007;104:766–773. (orange) vs Milrinone (blue) *p<0.05.1 6 7 Meta-analysis on mortality of ® …WITHOUT COMPROMISE levosimendan clinical trials in SIMDAX DOES ON LONG-TERM cardiology settings1 NOT DISTURB SURVIVAL RELAXATION... Study ID RR (95% CI)% Weight Adamopoulos 2006 0.44 (0.10, 1.89) 1.52 Berger 2007 0.79 (0.29, 2.13) 3.04 Bergh 2010 2.14 (0.20, 22.34) 0.60 The use of SIMDAX® was not Duygu 2008 1.54 (0.77, 3.07) 5.58 In a study by Jörgenssen et al. SIMDAX® not only Effects of levosimendan on relaxation time Duygu 2008 0.50 (0.21, 1.20) 3.76 associated with a decrease of Flevai 2006 1.50 (0.17, 13.23) 0.70 improved contractility whilst maintaining constant 90 Levosimendan Follath 2002 0.69 (0.46, 1.04) 11.28 heart rate and blood pressure, but also decreased Placebo survival. Ikonomidis 2007 0.17 (0.01, 3.13) 0.39 85 Kleber 2009 0.28 (0.01, 7.57) 0.31 isovolumic relaxation time.1 Levin 2009 0.32 (0.14, 0.71) 4.33 80 In fact, a meta-analysis of 23 studies Lileberg 2007 1.00 (0.02, 46.05) 0.23 describing the use of SIMDAX® in Mavrogeni 2007 0.25 (0.06, 1.06) 1.52 75 Mebazaa 2007 0.93 (0.78, 1.11) 20.65 cardiology settings show a risk Moiseyev 2002 0.72 (0.51,1.01) 13.68 70 Nieminen 2000 0.59 (0.04, 9.24) 0.44 ® reduction of 0.75 [SIMDAX Packer 2003 0.77 (0.22, 2.70) 1.99 65 441/2207 (20.0%), control 484/1893 Packer 2005 1.10 (0.84, 1.44) 16.62 Parissis 2007 0.50 (0.01, 24.33) 0.22 60 (25.6%), RR=0.75 (95% CI 0.63, Slawsky 2000 0.49 (-.10, 2.34) 1.32 Isovolumic relaxation time (ms) Trikas 2006 0.33 (0.08, 1.42) 1.51 55 0.91), p for effect: 0.003, p for Tziakas 2005 1.00 (0.02, 48.77) 0.22 heterogeneity: 0.131, NNT=18].1 Zairis 2004 0.51 (0.32, 0.81) 9.87 50 Zemljic 2007 1.00 (0.02, 47 97) 0.22 Baseline 0.1 µg/kg/min 0.2 µg/kg/min Overall 0.75 (0.63, 0.91) 100.00 (I 2 = 25.5%, p= 0.131) Effect of levosimendan vs placebo on Isovolumic relaxation time (IVRT) Reference: Reference: (mean±SEM) at maintained preload and afterload conditions after aortic valve 1. Landoni G et al. Crit Care Med. 2012;40:634–646. 0.00888 1 113 1. Jörgensen K et al. Circulation. 2008;117(8):1075–1081. replacement for aortic stenosis. *p<0.05.1 8 9 ...REDUCES …AND REDUCES MYOCARDIAL INJURY... HOSPITAL STAY Meta-analysis of the levosimendan effects on length of stay in hospital1 ® Current data suggest that SIMDAX also Effects of levosimendan on release of troponin These results are corroborated Study ID WMD (95% CI) Weight % diminishes myocardial injury.1,2 T during cardiac surgery by a meta-analysis of 8 studies Levosimendan ® Bergh CH 2010 -1.40 (-9.00, 6.20) 0.92 1.0 p=0.037 in which SIMDAX Placebo was used in cardiology settings: Duygu H 2008a 0.00 (-1.10, 1.10) 17.48 Duygu H 2008b -2.00 (-2.62, -1.38) 23.69 0.8 Length of stay in hospital was decreased by 1.59 days Follath F 2002 0.80 (-2.59, 4.19) 4.09 0.6 in SIMDAX® treated patients Mebazaa A 2007 -2.50 (-5.51, 0.51) 4.99 in addition to a significant Packer M 2013 -1.60 (-2.56, -0.64) 19.28 0.4 1 reduction in mortality. Parissis JT 2007 -2.60 (-3.63, -1.57) 18.28 Troponin T (µg/l) 0.2 Trikas A 2006 -2.00 (-3.71, -0.29) 11.27 Overall (I2=54.9% p=0.030) -1.59 (-2.33, -0.85) 100.00 0 End of Note: Weights are from random effects analysis Baseline procedure 24 hours 48 hours References: -9 0 9 1. Zangrillo A et al. J Cardiothorac Vasc Anesth. 2009;23:474–478. Troponin T levels up to 48 hours in cardiac surgery patients. Levosimendan 2. Eriksson H et al. Ann Thor Surg. 2009;87:448. (orange) vs placebo (grey). *p=0.032.2 Reference: 1. Landoni G et al. Crit Care Med. 2012;40:634–646 (electronic supplementary material). 10 11 PRODUCT INFORMATION: Simdax 2.5 mg/ml concentrate for solution for infusion. Therapeutic indications Hepatic impairment: Simdax must be used with caution Simdax infusion should be used cautiously in patients with Simdax is indicated for the short-term treatment of acu- in patients with mild to moderate hepatic impairment alt- tachycardia atrial fibrillation with rapid ventricular respon- tely decompensated severe chronic heart failure (ADHF) hough no dose adjustment appears necessary for these se or potentially life-threatening arrhythmias.
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