Levosimendan in heart failure

Dr Babu K Abraham MD, MRCP (UK), FICCM Director & Senior Consultant

Chennai Critical Care Consultants Department of Critical Care Medicine

Apollo Hospitals, Chennai

Levosimendan

A calcium sensitizer & inodilator Pharmacological effects

increased cardiac contractility vasodilation cardioprotection

Mainly for iv use In monitored hospitalized patients Most commonly used in acutely decompensated heart failure

Introduction

Reported Clinical Effects are Improved haemodynamics With no significant increase in oxygen consumption ↓ of symptoms of AHF Beneficial effect on neurohormone levels Sustained efficacy due to formation of an active metabolite Effective in patients under beta-blockade Predictable safety profile No development of tolerance

Lancet 2002; 360: 196-202 JAMA 2007; 297:1883-91 Heart, Lung and Vessels. 2013;5:227-245

Clinical Uses Reported

Acute decompensation of heart failure (ADHF) Advanced chronic heart failure Cardiac cardiac surgery Right heart failure Cardiogenic shock Septic shock Non cardiac surgery

ALARM- HF Intensive Care Med 2011; 37: 290-301

LIDO Lancet 2002; 360: 196-202

LevoRep Eur J Heart Fail 2014;16, 898–906

REVIEVE I & II II - JCHF 2013; 1: 103-11

RUSSLAN Eur Heart J 2002; 23: 1422-32

SURVIVE JAMA 2007; 297:1883-91

Eur Heart J 2002;23:1422–1432

Lancet 2002; 360: 196–202

JAMA. 2007;297:1883-1891

J Am Coll Cardiol HF 2013;1:103–11 REVIVE II STUDY

Levosimendan in Acute worsening of Chronic HF (ADHF)

Therapeutic Efficiency

Haemodynamics

J Am Coll Cardiol 2000; 36: 1903-12 Heart, Lung and Vessels 2013;5:227-245

Effects seen within 5 min bolus Post levosimendan infusion

Effects are maintained up to 7-9 days With no signs of development of tolerance

Significant fall in bp REVIVE study identified SBP <100 mmHg or DBP <60 mmHg at baseline as a factor increasing mortality risk

Other clinical effects

Dyspnoea Improved when compared to placebo 1

No differnce when compared to group receiving dobutamine 2

Renal function – Improves serum creatinine Improves GFR 3

↓ in the rate of ARF (OR 0.26 *96% CI 0.12-0.60], p=0.002 4

Rapid and sustained decrease in ANP 5

Effects were maintained even in β blocker treated patients

Circulation 2000; 102: 2222-7 1

JCHF 2013; 1: 103-11 1

Lancet 2002; 360: 196-202 2

J Cardioth Vasc Anesth 2010; 24: 51-7 3

CardiovascTher2013; 31: 108-14 4

JAMA 2007; 297:1883-91 5

STUDIES MORTALITY

LIDO study Lancet 2002; 360: 196-202

Levo vs Dobut 8% vs 17% ( p = 0.049)

RUSSLAN Study Eur Heart J 2002; 23: 1422-32

Levo vs placebo 12% vs 20% ( p =0.031)

REVIVE II JCHF 2013; 1: 103-11

Levo vs placebo 15% vs 12% (p = 0.21)

SURVIVE JAMA 2007; 297:1883-91

Levo vs Dobut 26% vs 28% ( p =0.40)

Meta-analyses CCM 2012; 40: 634-46

17.4% vs23.3% risk ratio [RR]: 0.80 p < .001 NNT 17

Varying reports Hospitalization and readmissions have been lower

Mortality

CCM 2012; 40:634–646

5,480 patients and 45 studies included The use of levosimendan was associated with a significant reduction in mortality 17.4% vs23.3% risk ratio [RR]: 0.80 [0.72; 0.89] p for effect< .001 NNT 17

Crit Care Med 2012; 40:634–646

Length of hospital stay was reduced in the levosimendan group (weighted mean difference [WMD] -1.31 [-1.95; -0.31], p for effect = .007, Q 56.15, p for heterogeneity < .0001, I 2 71% with 17 studies included

Adverse Effects & Safety Profile Generally well tolerated Hypotension

Use with caution in low bp Especially in case of hypovolaemia REVIVE study showed a low baseline bp as a factor increasing mortality risk

AF Higher incidence of AF relative to both placebo or dobutamine

Ventricular arrhythmia

Occasionally seen

Generally very safe drug to use

But has to be given under monitoring Follow-up need to be prolonged due to active metabolite

Lancet 2002; 360: 196-202 Eur Heart J 2002; 23: 1422-32 JCHF 2013; 1: 103-11 JAMA 2007; 297:1883-91

Heart, Lung and Vessels. 2013; 5(4): 227-245

Dosing guidance for levosimendan in ADHF

Levosimendan in advanced chronic heart failure

Until recently multiple small studies Results suggest that levosimendan improves

haemodynamics neurohormones clinical outcomes

Optimal dosing scheme not established LevoRep - a large prospective, double-blind, placebo-controlled, multicentre, parallel-group RCT- 2014

Am J Cardiol 2005;95:768-71 Heart 2006; 92: 1768-72 J Card Fail 2007; 13: 556-9 Heart Lung Circ 2008; 17: 206-10 Int J Cardiol 2011; 159: 225-9

Eur J Heart Fail 2014;1:6898–906

120 pts with advanced HF (EF ≤35%, NYHA class III or IV)

Levo (0.2 μg/kg/min) vs placebo Administered for 6 h at 2-week intervals over 6 weeks, in addition to standard care therapy Primary end point –

≥20% improvement in the 6MWT

≥15% score increase on the KCCQ

Secondary end point Event-free survival after 24 weeks Conclusion Intermittent ambulatory treatment with levosimendan in patients with advanced heart failure did not improve significantly functional capacity or quality of life as compared with placebo

LION-HEART, NCT01536132 LAICA, NCT00988806 ELEVATE, NCT01290146

Levosimendan in sepsis

Encouraging results from animal models of sepsis Results are still controversial In humans – several case series & few small RCTS Evidence enough to sustain the hypothesis that levo might be a promising therapy in severe sepsis and septic shock LeoPARDS study - ISRCTN12776039 516 pts enrollment completed

CCM 2007;35:1376–82 Crit Care 2011;15:R166 J Crit Care 2015;30: 908–913 Med Sci Monit, 2016; 22: 1486-1496

J Crit Care 2015;30:908–913

Meta analysis of the 7 RCTs Pts with severe sepsis or septic shock All compared levosimendan to a control All had mortality data Total of 246 patients All administered levosimendan as a 24-hour continuous infusion (0.17 ± 0.05 μg/ kg/ min) without a bolus All except one study compared levosimendan to Dobutamine One study compared levosimendan to standard care

Levosidemin reduced mortality compared with standard inotropic therapy 47% vs 61%; risk difference = −0.14, risk ratio = 0.79 *0.63- 0.98], P = .03, NNT = 7

J Crit Care 2015;30:908–913

Levosimendan in cardiac surgery

Heart, Lung and Vessels 2013;5:227-245 CCM 2011; 39: 2263-70 Br J Anaesth 2009; 102:198-204 AnesthAnalg 2007; 104: 766-73

Multiple studies showing Physiological benefits Myocardial protection Improved tissue perfusion Reduction in tissue damage

Superior to traditional inotropes

Sustained improvement in hemodynamics Decreasing myocardial injury

Outcomes Placebo controlled RTs have shown

Reduction in CPB time Reduction in length of ICU stay Improvement in hemodynamics Reduction in mortality

HSR-LEVO - NCT00994825 CHEETAH Study

Critical Care 2011, 15:R140

Risk of mortality with subgroups elective and emergency revascularisation1

Int J Cardiol 2015 Apr 24;184:323-36

Recent European Expert opinion – For the pre and peri op use of Levosimendan in cardical surgery

“The panelists recommended preoperative use of levosimendan in patients with generally compromised myocardial function, including right ventricular dysfunction. They advised against a bolus dose when used outside the operation room. The day prior to surgery was suggested as the optimal time point for initiation of a preoperative therapy with levosimendan. The recommended dose of levosimendan agreed upon was 0.1 μg/kg/min infusion for 24 h, or to the end of the vial. When levosimendan infusion is started during or after induction of anaesthesia, the addition of a bolus is considered to be a feasible option”

Levosimendan in Non – Cardiac Surgery

Neth J Med 2008; 66: 154-9 Eur J Anaesthesiol 2008; 25: 627-33 Curr Drug Targets 2009; 10:863-71

Multiple small studies Drug is Safe Improvements in ejection fraction Improvements in range of haemodynamic

Suggestion that the prophylactic administration of levosimendan in patients with compromised myocardial physiologic reserve, undergoing anesthesia and major non-cardiac surgery, is safe and advisable for preoperative cardiac optimization

Levosimendan in right ventricular failure

Multiple small studies Included RVH from various causes Used varying dosing schedule Levosimendan shown to: 1) reduce the increased RV afterload 2) Improve RV contractility 3) improve RV diastolic function

Am J Cardiol 2006; 98: 1489-92 Crit Care Med 2006; 34: 2287-93 J Clin Pharmacol 2009; 49: 109-15 Crit Care Med 2009; 37: 3017-23

Data still scarce Drug appears to be safe May improve some haemodynamics Small study (n=32)

Showing improved survival 30 day survival 69% with levosimendan vs 37% with enoximone; p=0.023

Current dataset is too small to draw definitive conclusions.

Levosimendan in cardiogenic shock

Circulation 2004; 110: 478

Int J Cardiol 209 (2016) 77–83

The existing meta-analyses, now based on a population of over 6000 patients, provide the general message of significant benefits for levosimendan in terms of patient mortality. The weight of evidence is now clearly in favour of usefulness/efficacy of levosimendan, with data from multiple randomized trials and meta-analyses.

Conclusion

Unique pharmacologic and pharmacodynamic properties Infusion enhances LV performance decreases LV filling pressure Decreases plasma BNP concentrations No increase myocardial oxygen consumption Has profound vasodilatory effects

Associated with symptomatic benefit Neither age nor gender influence the responses A 24 h infusion results in a prolonged haemodynamic effect- lasting for at least 7 days Effects not affected concomitant beta-blocker use There could be significant mortality benefit

It outperforms dobutamine in betablocked patients and in patients ADHF Safety

Levosimendan infusion has generally been well tolerated Hypotension most common side effect Caution advised when used in patients with low blood pressure Hypovolaemia Higher incidence of AF Follow-up may need to be prolonged, due prolonged duration of acction