This document provides information on levosimendan, a calcium sensitizer used in the management of congestive heart failure. It discusses levosimendan's mechanism of action of enhancing cardiac contractility without increasing intracellular calcium levels. This reduces the drug's potential for arrhythmias compared to other inotropes. The document summarizes levosimendan's pharmacokinetics, dosing, efficacy demonstrated in clinical trials compared to dobutamine and placebo, and side effect profile. It positions levosimendan as an ideal agent for increasing cardiac output while minimizing oxygen demand, tachyphylaxis and arrhythmogenic potential.

1. LEVOSIMENDAN

2. INTRODUCTION
One of the strategies used in the management of congestive heart
failure is to increase myocardial contractility without increasing the
afterload.
“Inodilators”, as their name suggest, are a group of drugs that achieve
this dual goal by increasing the contractility and causing
vasodilatation.
This group includes dobutamine (β- adrenergic agent) and milrinone
(phosphodiesterase III inhibitor).

3. These agents achieve these effects by increasing intracellular
concentrations of free
calcium.
However, this action markedly increases myocardial energy
consumption, which may
contribute to the risk of arrhythmias.
Levosimendan is one of a new class of inodilators, the calcium
sensitizers.

4. Current IV Treatments for
Acute Heart Failure
• Diuretics
• Other agents (inotropes)
• ß-receptor agonists
(dobutamine, dopamine)
• PDE inhibitors (milrinone)
• Nitrates and/or any other IV
vasodilators
Preload
Contractility
Afterload
4

5. Inotropic drugs
Gs Gi
β-receptor
ATP cAMP (active)
rise in intracellular
calcium
Dobutamine
AMP (inactive)
PDE
Na+/Ca2+
exchanger
Na+/K+exchanger
[Ca2+]
[Na+]
[K+]
Digoxin
Milrinone
5

6. MECHANISM OF ACTION
Levosimendan is a pyridazone-dinitrile derivative.
It has two important actions. Its primary action is to enhance cardiac
contractility. This is achieved by a pharmamcological mechanism known as
calcium sensitization.
It does not increase intracellular concentrations of free calcium. It binds to
cardiac troponin C in a calcium-dependent manner and stabilises troponin C.
This causes actin-myosin cross-bridges, without increasing myocardial
consumption of adenosine triphosphate (ATP).
The cardiac performance and contractility are significantly inproved with no
increase in the total myocardial energy demand and oxygen consumption.
The potential for arrhythmia is also reduced as total intracellular calcium
levels are not raised.

7. Stabilization effect is calcium dependant and levosimendan exerts
it effects during systole; it does not effect the duration of diastole and
so ventricular relaxation is not impaired.
Consequently adequate ventricular filling and optimal coronary
perfusion still occurs.
Levosimendan also causes venous, arterial and coronary vasodilation,
probably by opening ATPsensitive potassium channels in smooth
muscle.
Dose-dependant hypotension may occur. Levosimendan is also of
benefit in the setting of pulmonary vasoconstriction and right
ventricular dysfunction and reduces pulmonary vascular
resistance.

8. Levosimendan
Levosimendan increases calcium myofilament responsiveness by directly
affecting contractile proteins to increase contractility without increasing
intracellular calcium concentrations
(2) it opens KATP channels in myocytes & SM cells
act as a vasodilator ( anti-ischemic and antistunning effects)
(1) Enhances calcium myofilament responsiveness by
binding to cardiac troponin C
increases contraction
(functions as a calcium sensitizer)
Dual mechanism of action:

9. key differentiating property of levosimendan
- does not increase intracellular levels of cAMP or calcium
- does not cause increased myocardial oxygen consumption
- Opens KATP channels in myocytes and vascular SM cells
- results in vasodilatation and cardio protection
- reduces preload and after load
- increased blood flow to organs
(including increased coronary blood flow)
- anti-ischemic and antistunning effects
Loading dose - 12µ g/kg applied over 10 minutes
Continuous infusion- 0 .1 to 0.2 µg/kg per min over 24 hours

10. PHARMACOKINETICS
Levosimendan is 98% bound to plasma proteins and completely metabolized
prior to excretion.
Approxi-mately 5% of a dose is converted in the intestines, and then to a
highly-active metabolite
with an elimination half-life of 75–80 h (compared to 1 hour elimination half-
life for levosimendan itself).
This metabolite reaches a peak plasma concentration about 2 days after the
termination of the infusion and
exhibits haemodynamic effects similar to those of levosimendan.
Because of the long half-life of the active metabolite, these effects last for up
to 7 to 9 days after discontinuation of a 24-hour infusion of levosimendan.

11. DOSAGE
The usual dosage of intravenous levosimendan used in clinical trials of
patients with heart failure is 6 to 12 μg/kg loading dose over 10 minutes
followed by 0.05 to 0.2 μg/kg/min as a continuous infusion.
Hemodynamic response is generally observed within 5 minutes of
commencement of infusion of the loading dose.
Peak effects are observed within 10 to 30 minutes of infusion; duration of
action of levosimendan is about 75-78 hours to 1 week due to
active metabolites.
No dosage adjustments are required in patients with mild to moderate renal
failure and hepatic impair-ment.
Efficacy with once a week administration makes it a promising drug.
The published trials so far have utilized intravenous levosimendan. However,
the agent is also well absorbed orally and oral preparation is now available.

12. SIDE EFFECTS
Levosimendan is well tolerated, with most adverse
events (e.g., headache, hypotension) being dose related
and arising from the vasodilatory actions of the drug.
In order to avoid undue hypotension it may
be prudent to temporarily stop milrinone and other
vasodilators when administering this drug.
The other side effects that are forthcoming from trials
include prolongation of corrected QT interval and
rarely, ventricular tachycardia.
Nevertheless, it should be avoided in patients with Torsades or any
other abnormal rhythm.

13. Contraindications
Hypersensitivity to levosimendan or to racemic simendan
Levosimendan should not be used in either severe renal (creatinine
clearance <30mL/min) or severe hepatic impairment.
Severe hypotension and tachycardia
Significant mechanical obstructions affecting ventricular filling or
outflow or both
History of Torsades de Pointes

14. Precautions
Should be used cautiously in patients with tachycardia, atrial
fibrillation with rapid ventricular response or potentially life-
threatening arrhythmias
Should be used cautiously and under close ECG monitoring in
patients with ongoing coronary ischaemia, long QTc interval
regardless of aetiology, or when given concomitantly with medicinal
products that prolong the QTc interval
Hypotension
As excessive decrease in cardiac filling pressure may limit the
response to levosimendan, severe hypovolaemia should be corrected

15. If excessive changes in blood pressure or heart rate are observed, the rate of
infusion should be reduced or the infusion discontinued
Effects on blood pressure generally last for 3-4 days and the effects on heart
rate for 7-9 days. Non-invasive monitoring for at least 3 days after the end of
infusion or until the patient is clinically stable is recommended.
Hepatic dysfunction (reduced clearance) may lead to increased
concentrations of the metabolite, which may result in more pronounced and
prolonged haemodynamic effects
May cause a decrease in serum potassium concentration.
Levosimendan infusions of may be accompanied by decreases in
haemoglobin and haematocrit and caution should be exercised in patients
with ischaemic cardiovascular disease and concurrent anaemia

16. Short-Term Use of Inodilator Treatment
-Dobutamine v/s Levosimendan
Levosimendan V/s Dobutamine:
- LIDO trial
- CASINO trial
- SURVIVE –W trial

17. Levosimendan Infusion versus Dobutamine
(LIDO) studyLevosimendan Infusion versus Dobutamine (LIDO) study

18. Kaplan–Meier survival analysis in the LIDO
The prospective benefit observed at 31 days for Levosimendan-treated
patients was maintained through the 180-day follow-up period.

19. Calcium Sensitizer or Inotrope or None in Low-Output Heart
Failure Study (CASINO)
Dobutamine was associated with lower 6-month survival compared with
Levosimendan or placebo in patients with decompensated low output HF
- enrolled 600 patients hospitalized with NYHA class IV HF
- randomized to Levosimendan, Dobutamine, or placebo 48 hrs after presentation
- primary end point of the study was mortality at one month, 6 months, or 1 yr
Heart Failure Update 2004 and Eur J Heart Fail

20. Survival curves for the three treatment arms of the CASINO study
before complete follow-up of patients

21. Randomized Multicenter Evaluation of Intravenous Levosimendan
Efficacy Versus Placebo in the Short-Term Treatment of
Decompensated Heart Failure (REVIVE)
- large-scale, placebo-controlled, double-blind study
- in 600patients hospitalized for AHFS with LVEF <0.35 & dyspnea
at rest who required intravenous diuretics
- Randomized to receive either Levosimendan or placebo in
addition to standard therapy
REVIVE-1 data ( n=100) - Levosimendan treatment A/W
- improvement in the composite end point at 24 hrs and 5 days
- a significant reduction in BNP levels at 24 hours and 5 days
- shorter lengths of initial hospitalization

23. Randomized Study on Safety and Effectiveness of Levosimendan in Patients
with Left Ventricular Failure Due to an Acute Myocardial Infarction (RUSSLAN)
LEVOSIMENDAN

24. Randomized Study on Safety and Effectiveness of Levosimendan in Patients
with Left Ventricular Failure Due to an Acute Myocardial Infarction (RUSSLAN)

25. Kaplan–Meier survival analysis in the RUSSLAN trial
The prospective survival benefit of Levosimendan compared to
placebo at 14 days were maintained through 180 days of follow-up

26. - indicated in patients with symptomatic low COP HF secondary to cardiac
systolic dysfunction without severe hypotension
ESC 2005 guideline on acute HF: Levosimendan
class IIa/ Level of evidence B

27. Levosimendan
Clinical Effect Ideal Agent LevosimendanPDE InhibitorsDobutamine
Cardiac Output
Heart Rate
Blood Pressure
Oxygen Demand
Arrhythmogenic Potential
Cardiac Filling Pressure
or
Tachyphylaxis
27

28. Levosimendan
• LIDO (Lancet 2002; 360:196-202)
- Benefit & safety better than standard inotrope in
ADHF
• RUSSLAN study (Eur Heart J 2002;23:1422-32)
– Safe & effective for patients with LV failure
complicating acute MI
• CASINO (Eur J Heart Fail 2004;6:673-6)
– Clear mortality benefit in favour of levosimendan
compared with dobutamine in class IV CHF patients
• REVIVE I trial (Crit Care 2004;8(suppl 1):P88)
– Levosimendan reduces length of intensive and
hospital day in patient with acute decompensated HF
28

29. Levosimendan for treatment of
acute decompensated heart failure
REVIVE II (Randomized Multicenter Evaluation of Intravenous
Levosimendan Efficacy Study)
(AHA Scientific Sessions 2005 Late Breaking Clinical Trials II)
 600 patients, 103 sites
 ADHF, dyspnoea at rest despite iv diuretics, LVEF <35%
 Levo bolus (6-12 mcg/kg) + 24-hour infusion (0.1-
0.2mcg/kg/min) vs placebo
 After 5 days, more Levo patients improved (19.4% vs 14.6%),
fewer Levo patients worsened (19.4% vs 27.2%)
 Significant BNP reduction in Levo arm at 24 hours & 5 days
 No difference in mortality at 90 days
29

30. Levosimendan for treatment of
acute decompensated heart failure
SURVIVE (Survival of Patients with Acute Heart Failure in Need
of Intravenous Inotropic Support Study)
(JAMA 2007; 297:1883-1991)
 1327 patients, 75 sites
 ADHF, LVEF <35%, clinical requirement for iv inotropic
therapy
 Levosimendan bolus + infusion vs dobutamine
 Reduction of mortality by 28% at 5 days and of 14% at 31
days in in Levo arm
 Effect greatest (42% reduction at 5 days) in patients with
previous heart failure
 Statistically non-significant but consistently lower mortality
at 6 months with Levo
30

31. Conclusions from
REVIVE II and SURVIVE
 Levosimendan represents an effective alternative to current
therapies for ADHF
 Short-term improvement in symptoms and clinical course,
associated with marked reduction in BNP
Mortality was numerically greater vs placebo but lower vs
dobutamine
AF was increased during 3- to 6-month FU period
VT was increased vs placebo but not increased vs
dobutamine
31

37. CONCLUSIONS
Prophylactic levosimendan did not result in a rate of the short-term
composite end point of death, renal-replacement therapy,
perioperative myocardial infarction, or use of a mechanical cardiac
assist device that was lower than the rate with placebo among
patients with a reduced left ventricular ejection fraction who were
undergoing cardiac surgery with the use of cardiopulmonary bypass.

38. LEVOSIMENDAN IN SEPTIC SHOCK
Studies have shown that myocardial dysfunction
is present in up to 60% of the patients with
septic shock and may not be apparent at initial
presentation.
Therefore, the majority of patients with septic shock could still be
expected to benefit from the inotropic effects of levosimendan, not to
mention its antiinflammatory, antioxidative, antiapoptotic, and
cardioprotective effects.
Such effects may offer additional systemic benefit, regardless of the
presence of myocardial
dysfunction.

39. KEY MESSAGES
• Levosimendan, a new inodilator, may be useful in refractory cardiac
failure, refractory pulmonary hypertension and dilated
cardiomyopathy.
• Levosimendan may help in decreasing the need for long term
inotropic support and may thus act as a bridge
to heart transport.
• Levosimendan with its long half-life appears to be a promising “once
a week” inotrope.

40. THANK YOU