SIMDAX ® GIVES YOU TIME IN ACUTE HEART FAILURE 1 SIMDAX® RELIEVES Improvement in clinical status Improved SYMPTOMS 20 p=0.015 19.4% 14.6% Levosimendan + SOC (n=299) IN AHF 10 Placebo + SOC (n=301) p=0.015 SIMDAX® improves symptoms of dyspnoea 0 and fatigue in acute heart failure. In the The primary endpoint result in the -10 REVIVE trial1, composite consisting Phase III regulatory study REVIVE, symptoms of patients’ subjective symptom -19.4% assessments (at 6 hours, 24 hours, over the 5-day assessment period improved -20 and 5 days) and signs of worsening -27.2% symptoms (including death) during significantly more with SIMDAX® than with Patients improved or worsened (%) the 5 days after starting drug -30 Worsened infusion. placebo when administered on top of the standard of care.1 Improvement in dyspnea 100 Generalized linear model p=0.018 Levosimendan + SOC (n=299) 90 Placebo + SOC (n=301) 80 Effects of levosimendan vs 70 placebo on top of standard of care on dyspnea in patients with AHF.4 60 Patients improved (%)* 6 hrs 24 hrs 48 hrs Day 3 Day 5 Reference: 1. Packer M. et al. JCHF. 2013;1(2): 103-11. *Includes mild, moderate and marked improvement on a 7-point scale 2 …WITH SUSTAINED HEMODYNAMIC AND Levosimendan + SOC (n=299) NEUROHORMONAL EFFECTS Placebo + SOC (n=301) The hemodynamic effects of SIMDAX® Sustained hemodynamic effects on cardiac output (CO) and pulmonary 1 CO (L/min) Max capillary wedge pressure (PCWP) have been End PCWP (mmHg) 0 1-3 24-hr infusion Figure 1: Duration of action of shown in several clinical trials. End -1 24-hour infusion of levosimendan.1 1,4 CO = Cardiac Output; The effect of SIMDAX is sustained, as PCWP = pulmonary capillary wedge -2 also seen in a prolonged decrease of brain pressure natriuretic peptide in the SURVIVE clinical -3 Max trial.4 Differences in AUC of CO and PCWP -4 2 6 24 2 3 5 7 9 14 Hours Days Levosimendan + SOC (n=299) Sustained effects on neurohormone levels Placebo + SOC (n=301) Levosimendan 0 Dobutamine -200 p<0.001 at all timepoints Figure 2: Rapid and sustained -400 reduction in B-type natriuretic peptide. In SURVIVE, a double- blind randomized, multicenter -600 Mean change study comparing levosimendan References: 1. Lilleberg J et al. Eur Heart J. 1998;19:660–668. and dobutamine in 1327 patients 2. Follath F. et al. Lancet. 2002;360:9328):196-202. 196-202. from baseline (pg/ml) -800 hospitalized for AHF, a more 3. Kivikko M et al. Circulation. 2003 Jan 7;107(1):81-6. 0 1 2 3 4 5 profound reduction in BNP was 4. Mebazaa A. et al. JAMA. 2007;297(17):1883-91. seen with levosimendan.4 Days since start of drug infusion 3 p=0.01 …THE BENEFITS ARE ∆CO 1.5 (l/min) PRONOUNCED IN THE 1.0 0.5 ß- ß+ ß- ß+ PRESENCE OF β-BLOCKERS 0 Levosimendan Dobutamine 0 ß- ß+ ß- ß+ -2 1 In the ESC heart failure guidelines -4 ® SIMDAX is recommended for -6 Effect of previous beta-blocker use on ∆PCWP acute heart failure in patients with cardiac output (CO) and pulmonary (mmHg) -8 capillary wedge pressure (PCWP) after p=0.03 reduction of cardiac output and in a 24-hour infusion of levosimendan or dobutamine at 24 hours post-baseline ß– without ß-blockers 1 presence of β-blockers. (LIDO)2 ß+ with ß-blockers SIMDAX® can be used in patients Favours Deaths, N (%) P-value receiving beta-blocking agents Use of Day -blocker Levosimendan Dobutamine Levosimendan Dobutamine HR Interaction without loss of efficacy.2 5 (1.5) 17 (5.1) 0.01 0–5 Yes 0.03 Indeed a beneficial effect on 31 days No 24 (7.3) 23 (7.0) 0.87 survival is also noticeable in presence 0–14 Yes 15 (4.5) 25 (7.5) 0.10 3 0.16 of β-blockers. No 44 (13.4) 44 (13.3) 1.00 24 (7.1) 31 (9.3) 0.29 0–31 Yes 0.55 No 55 (16.8) 60 (18.2) 0.62 0.1 0.5 1 2 10 Hazard ratio (95 % CI) References: 1. Ponikowski P et al. Eur Heart J 2016;37:2129-2200. 2. Follath F. et al. Lancet. 2002;360:9328):196-202. 196-202. Hazard ratios for all-cause mortality rates up to 31 days after levosimendan and dobutamine therapy (SURVIVE) stratified for beta-blocker use at the start of the study.2 3. Mebazaa A et al Eur J Heart Fail. 2009;11(3):304-11. 4 HOW TO USE SIMDAX® IN AHF What to expect? Haemodynamic and neurohormonal effects Example of use Pulmonary capillary wedge pressure AHF patients with systolic dysfunction (LVEF < 40%) and with the following Cardiac output (index) ­­­ characteristics may be considered for SIMDAX® treatment: Stroke volume • signs of hypoperfusion, i.e. cool extremities, oliguria Systemic vascular resistance • severe pulmonary oedema Pulmonary vascular resistance ® • inadequate response to traditional treatment (however, the start of the SIMDAX infusion Natriuretic peptide levels should not be unnecessarily delayed.) Exclusion criteria = decrease, = increase • severe hypotension and/or tachycardia • severe renal impairment Other clinical effects • severe hepatic impairment Relief of symptoms of heart failure • history of Torsades de Pointes Effects maintained also with beta-blockers Dosing Sustained effects due to an active metabolite Dosing of SIMDAX® will be according to the SPC. However, the bolus dose No development of tolerance should only be given if immediate effects are needed and the baseline blood No increase in myocardial oxygen consumption pressure is > 120 mmHg.1 Thus, in most cases: Anti-ischemic effect ® • SIMDAX -infusion will be started with an infusion rate of 0.1 mcg/kg/min. No impairment of diastolic function • The rate can be increased to 0.2 mcg/kg/min if further effect is warranted or decreased to 0.05 mcg/kg/min if adverse effects (e.g. hypotension) occurs. • The maximum duration of the infusion should not exceed 24 hours. Reference: 1. Nieminen MS et al. Heart Lung Vessels. 5 IN AHF THE EFFECTS OF SIMDAX® ALLOW A SHORTER HOSPITAL STAY SIMDAX®, on top of standard of care, shortens Hospital stay is reduced by hospital stay in acute heart failure. These data have been shown in a phase III study (vs placebo).1,2 1.92 DAYS Hospitalization length of acute heart failure patients ∆=-1.92 p=0.008 Levosimendan 7.03 Placebo 8.96 0 1 2 3 4 5 6 7 8 9 10 Duration of initial hospitalization (days) References: 1. De Lissovoy G et al. Eur J Health Econ. 2010;11:185– Data from an economic analysis of the REVIVE II study of 600 patients 193. 2. Packer M et al. JACC Heart Fail. 2013;1(2):103-11 hospitalized for treatment of acute decompensated heart failure.1 6 ...WHICH IS CONFIRMED BY META-ANALYSIS OF SEVERAL STUDIES These results are corroborated Meta-analysis of the levosimendan effects on length of stay in hospital1 by a meta-analysis of 8 studies Study ID WMD (95% CI) Weight % in which SIMDAX® was used in cardiology settings: Bergh CH 2010 -1.40 (-9.00, 6.20) 0.92 Length of stay in hospital Duygu H 2008a 0.00 (-1.10, 1.10) 17.48 was decreased by 1.59 days Duygu H 2008b -2.00 (-2.62, -1.38) 23.69 ® in SIMDAX treated patients Follath F 2002 0.80 (-2.59, 4.19) 4.09 in addition to a significant Mebazaa A 2007 -2.50 (-5.51, 0.51) 4.99 reduction in mortality.1 Packer M 2013 -1.60 (-2.56, -0.64) 19.28 Parissis JT 2007 -2.60 (-3.63, -1.57) 18.28 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 Note: Weights are from random effects analysis -9 0 9 Reference: 1. Landoni G et al. Crit Care Med. 2012;40:634–646 (electronic supplementary material). 7 BETTER OUTCOME THAN WITH OTHER VASOACTIVE I.V. AGENTS Registry study in patients ALARM-HF1 registry 60 with acute heart failure The effect of i.v. vasoactive drugs on in-hospital Epinephrine 50 mortality was studied in 4.953 AHF patients (Figure 1. unadjusted analysis). Norepinephrine 40 A propensity-based analysis was performed to compare in-hospital mortality of patients 30 treated only with SIMDAX® versus those treated Dopamine with only catecholamines showing a significant Dobutamine 20 reduction in the risk of in-hospital mortality Diuretics Whole cohort (HR 0.25, 95% CI 0.07–0.85). In-hospital mortality (%) 10 Levosimendan Vasodilators 0 0 5 10 15 20 25 30 Days Reference: 1. Mebazaa A et al. Intensive Care Med. Figure 1: Effect of the main intravenous (IV) drugs administered during first 48 h 2011;37:290-301. in acute heart failure (AHF) patients on in-hospital mortality. 8 ...WITH NO COMPROMISE Meta-analysis on mortality of levosimendan ON LONG-TERM clinical trials in cardiology settings1 SURVIVAL Study ID RR (95% CI)% Weight Adamopoulos 2006 0.44 (0.10, 1.89) 1.52 The use of SIMDAX® was associated with Berger 2007 0.79 (0.29, 2.13) 3.04 improved survival. Bergh 2010 2.14 (0.20, 22.34) 0.60 Duygu 2008 1.54 (0.77, 3.07) 5.58 Duygu 2008 0.50 (0.21, 1.20) 3.76 A meta-analysis of 23 studies describing Flevai 2006 1.50 (0.17, 13.23) 0.70 the use of SIMDAX® in cardiology settings Follath 2002 0.69 (0.46, 1.04) 11.28 Ikonomidis 2007 0.17 (0.01, 3.13) 0.39 ® showed a 25% risk reduction [SIMDAX Kleber 2009 0.28 (0.01, 7.57) 0.31 441/2207 (20.0%), control 484/1893 Levin 2009 0.32 (0.14, 0.71) 4.33 Lileberg 2007 1.00 (0.02, 46.05) 0.23 (25.6%), RR=0.75 (95% CI 0.63, 0.91), Mavrogeni 2007 0.25 (0.06, 1.06) 1.52 p for effect: 0.003, p for heterogeneity: Mebazaa 2007 0.93 (0.78, 1.11) 20.65 1 Moiseyev 2002 0.72 (0.51,1.01) 13.68 0.131, NNT=18].